Aminopyrimidine Kinase Inhibitors

ABSTRACT

Disclosed are compounds, pharmaceutical compositions containing those compounds, and uses of the compounds and compositions as modulators of casein kinase 1 (e.g., CK1γ), casein kinase 2 (CK2), Pim1, Pim2, Pim3, the TGFβ pathway, the Wnt pathway, the JAK/STAT pathway, and/or the mTOR pathway. Uses are also disclosed for the treatment or prevention of a range of therapeutic indications due at least in part to aberrant physiological activity of casein kinase 1 (e.g., CK1γ), casein kinase 2 (CK2), Pim1, Pim2, Pim3, the TGFβ pathway, the Wnt pathway, the JAK/STAT pathway, and/or the mTOR pathway.

RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalPatent Application Ser. No. 61/289,685, filed Dec. 23, 2009; and U.S.Provisional Patent Application Ser. No. 61/324,481, filed Apr. 15, 2010.

BACKGROUND OF THE INVENTION

Casein kinase 1 (CK1) is a family of evolutionarily conservedserine/threonine kinases including seven known members in vertebrates(CK1α, -β, -γ1, -γ2, -γ3, -δ and -ε). The CK1s contain a typical kinasedomain followed by a C-terminal tail region, which has been implicatedin the regulation of CK1 localization, substrate selectivity and kinaseactivity. Myriad proteins have been found to be phosphorylated by CK1s,which are involved in a wide range of cellular functions includingvesicular trafficking, DNA damage repair, cell cycle progression,cytokinesis and circadian rhythms (reviewed by Gross and Anderson(1998); Vielhaber and Virshup (2001); Knippschild et al. (2005)).Moreover, CK1 family members (-α, -δ/ε and -γ) modulate the activitiesof major signaling pathways (for example, Wnt and Shh) through severalmechanisms (Peters et al., 1999; Liu et al., 2002; Price and Kalderon,2002; Davidson et al., 2005; Zeng et al., 2005 and reviewed by Price(2006)).

In mammals seven CK1 isoforms, namely CK1α, γ, γ₁₋₃, δ and ε, andseveral splice variants have been described. They all contain a highlyconserved kinase domain, a short N-terminal domain of 6 to 76 aminoacids and a highly variable C-terminal domain of 24 to more than 200amino acids. The constitutive phosphotransferase activity of CK1isoforms is tightly controlled by several mechanisms. For example, theclosely related isoforms CK1δ and ε, which share a 98% identity at theamino acid level in their catalytic domain, are regulated byautophosphorylation, dephosphorylation and proteolytic cleavage. Membersof the CK1 family are found in the nucleus, the cytoplasm and in theplasma membrane. By phosphorylating many different substrates bearingeither a canonical or non-canonical consensus sequence they modulate theactivity of key regulator proteins involved in many cellular processessuch as cell differentiation, cell proliferation, apoptosis, circadianrhythm, chromosome segregation, and vesicle transport.

The Pim kinase family contains three isoforms, Pim-1, Pim-2 and Pim-3,and has recently emerged as targets of interest in oncology and immuneregulation. Ongoing studies have identified a role for these proteins incell survival and proliferation, both functionally and mechanistically,and overexpression has been observed in a number of human cancers andinflammatory states.

Pim kinases suppress apoptosis and regulate cell-cycle progression.Elevated levels of Pim kinases have been reported in solid tumors suchas prostate cancer and pancreatic cancer. Pim-1 was initially discoveredin murine leukemia and several independent studies have shown thiskinase to be upregulated in human prostate cancer. Pim-1, 2 and 3 makeup a distinct and highly homologous family of serine/threonine kinasesbelonging to the calmodulin-dependent protein kinase-related (CAMK)family. In addition to the three gene-encoded proteins, translationalvariants have also been reported for Pim-1 and 2 resulting fromutilization of alternative start codons. The name Pim refers to theoriginal identification of the pim-1 gene as a frequent proviralinsertion site in Moloney murine leukemia virus-induced T-celllymphomas, and the gene encoding Pim-2 was subsequently found to havesimilar susceptibility. Pim-3, originally designated kinase induced bydepolarization (KID)-1, was later renamed due to high sequencesimilarity to Pim-1 (71% identity at the amino acid level). Consideringall three isoforms, Pim proteins are widely expressed with high levelsin hematopoietic tissue and are aberrantly expressed in a variety ofhuman malignancies. Pim kinases positively regulate cell survival andproliferation, affording therapeutic opportunities in oncology. The Pimprotein kinases are frequently overexpressed in prostate cancer andcertain forms of leukemia and lymphoma.

A role for Pim kinases in immune regulation has also been observed.Pim-2 has been reported to have enhanced levels of expression in avariety of inflammatory states and may function as a positive regulatorof interleukin-6 (IL-6), whereby overexpression of the kinase augmentsstimulus-induced IL-6 levels. Pim-1 and 2 have also been implicated incytokine-induced T-cell growth and survival. Comparing the sensitivityof stimulated T cells from Pim-1−/−Pim-2−/− mice to wild-type micefollowing treatment with the immunosuppressant rapamycin, it was foundthat T-cell activation was significantly impaired by Pim-1/Pim-2deficiency, suggesting that Pim kinases promote lymphocyte growth andsurvival through a PI3K/AKT (PKB, protein kinase B)/mammalian target ofrapamycin (mTOR)-independent pathway. Other parallel but independentfunctions and overlapping substrate specificity for proteins in thesepathways have been reported as well, including the positive regulationof transcription of nuclear factor kappa-B (NF-κB)-responsive genes,which have implications in both inflammation and oncology. Therefore,Pim kinases are attractive targets for both therapeutic areas. Further,Pim kinases have been reported to play a role in the protection of theATP-binding cassette (ABC) transporter P-glycoprotein (Pgp; ABCB1) fromproteolytic and proteasomal degradation. Pgp is known to mediate drugefflux and as such, inhibitors of Pim kinases may provide a novelapproach to abrogating drug resistance.

SUMMARY OF THE INVENTION

An aspect of the present invention relates to compounds that inhibitcasein kinase 1 and/or casein kinase 2 and/or a PIM kinase. For example,an embodiment relates to a compound of formula 1:

or a pharmaceutically acceptable salt thereof, wherein independently foreach occurrence:W and X are independently oxygen or sulfur;Z¹, Z² and Z³ are independently C—R²⁰ or N, provided that at least oneof Z¹ and Z² is N;R¹ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl,heterocyclylalkyl, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷),—SO₂N(R⁶)(R⁷), and —[C(R⁴)₂]_(p)—R⁵;R² and R³ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶,—C(O)OR⁶, —SO₂(R⁶), —C(O)_(N)(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), —P(O)(OR⁶)(OR⁷);or R² and R³ are joined together to form an optionally substitutedheterocyclic ring;R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl,halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl;R⁵ is selected from the group consisting of aryl, heteroaryl,heterocyclyl, —N(R⁸)(R⁹), —N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R⁸)SO₂(R⁹),—CON(R⁸)(R⁹), —OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR⁹,—C(O)N(OH)(R⁸), —OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR⁸,—OP(O)(OR⁸)(OR⁸), —P(O)(OR⁸)(OR⁸) and —N(R⁸)P(O)(OR⁹)(OR⁹);R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl;R⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl; or R⁶ and R⁷ are joined together to form aheterocyclic ring;R⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl;R⁹ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl; or R⁸ and R⁹ are joined together to form aheterocyclic ring;R²⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl,heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl,perfluoroalkyl, thio, cyano, hydroxy, methoxy, alkoxy, phenoxy, aryloxy,heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino,arylamino, heteroarylamino, amido, acylamino, sulfate, sulfonate,sulfonyl, sulfoxido, sulfonamido, sulfamoyl, —[C(R⁴)₂]_(p)—R⁵, NR¹⁴R¹⁵,OR¹⁶, O—[C(R⁴)₂]_(p)—R⁵, NR¹⁴—[C(R⁴)₂]_(p)—R⁵ and SR¹⁶;R¹⁴ and R¹⁵ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶,—C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —P(O)(OR⁶)(OR⁷);or R¹⁴ and R¹⁵ are joined together to form an optionally substitutedheterocyclic ring;R¹⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl,heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, and —C(O)N(R⁶)(R⁷); andp is 1, 2, 3, 4, 5, or 6;

wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkylmay be optionally substituted.

An embodiment relates to a compound of formula 2:

or a pharmaceutically acceptable salt thereof, wherein independently foreach occurrence:R¹ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl,heterocyclylalkyl, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)_(N)(R⁶)(R⁷),—SO₂N(R⁶)(R⁷), and —[C(R⁴)₂]_(p)—R⁵;R² and R³ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶,—C(O)OR⁶, —SOAR), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷)—P(O)(OR⁶)(OR⁷); or R²and R³ are joined together to form an optionally substitutedheterocyclic ring;R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl,halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl;R⁵ is selected from the group consisting of aryl, heteroaryl,heterocyclyl, —N(R⁸)(R⁹), —N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R⁸)SO₂(R⁹),—CON(R⁸)(R⁹), —OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR^(S),—C(O)N(OH)(R⁸), —OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR⁸,—OP(O)(OR⁸)(OR⁹), —P(O)(OR⁸)(OR⁹) and —N(R⁸)P(O)(OR⁹)(OR⁹);R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl;R⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl, or R⁶ and R⁷ are joined together to form aheterocyclic ring;R⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl;R⁹ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl; or R⁸ and R⁹ are joined together to form aheterocyclic ring;R²⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl,heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl,perfluoroalkyl, thio, cyano, hydroxyl, methoxy, alkoxy, phenoxy,aryloxy, heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino,alkylamino, arylamino, heteroarylamino, amido, acylamino, sulfate,sulfonate, sulfonyl, sulfoxido, sulfonamido, sulfamoyl,—[C(R⁴)₂]_(p)—R⁵; NR¹⁴R¹⁵, OR¹⁶, and SR¹⁶;R¹⁴ and R¹⁵ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶,—C(O)OR⁶, —SO₂(R⁶), —C(O)_(N)(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and—P(O)(OR⁶)(OR⁷); or R¹⁴ and R¹⁵ are joined together to form anoptionally substituted heterocyclic ring;R¹⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl,heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, and —C(O)N(R⁶)(R⁷); andp is 1, 2, 3, 4, 5, or 6;

wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkylmay be optionally substituted.

An aspect of the invention relates to a compound, or a pharmaceuticallyacceptable salt thereof, selected from the group consisting of:

An aspect of the invention relates to a compound, or a pharmaceuticallyacceptable salt thereof, selected from the group consisting of:

An embodiment relates to any one of the aforementioned compounds,wherein the compound is an inhibitor of CK1, CK1γ1, CK1γ2, or CK1γ3. Inone embodiment the compound has an IC₅₀ of less than 5000 nM for CK1,CK1γ1, CK1γ2, or CK1γ3. In one embodiment the compound has an IC₅₀ ofless than 1000 nM for CK1, CK1γ1, CK1γ2, or CK1γ3. In one embodiment thecompound has an IC₅₀ of less than 500 nM for CK1, CK1γ1, CK1γ2, orCK1γ3.

An embodiment relates to any one of the aforementioned compounds,wherein the compound is an inhibitor of CK2. In one embodiment thecompound has an IC₅₀ of less than 5000 nM for CK2. In one embodiment thecompound has an IC₅₀ of less than 1000 nM for CK2. In one embodiment thecompound has an IC₅₀ of less than 500 nM for CK2.

An embodiment relates to any one of the aforementioned compounds,wherein the compound is an inhibitor of PIM1, PIM2, or PIM3. In oneembodiment the compound has an IC₅₀ of less than 5000 nM for PIM1, PIM2,or PIM3. In one embodiment the compound has an IC₅₀ of less than 1000 nMfor PIM1, PIM2, or PIM3. In one embodiment the compound has an IC₅₀ ofless than 500 nM for PIM1, PIM2, or PIM3.

An embodiment relates to any one of the aforementioned compounds,wherein the compound is an inhibitor of the Wnt pathway.

An embodiment relates to any one of the aforementioned compounds,wherein the compound is an inhibitor of the TGFβ pathway.

An embodiment relates to any one of the aforementioned compounds,wherein the compound is an inhibitor of the JAK/STAT pathway.

An embodiment relates to any one of the aforementioned compounds,wherein the compound is an inhibitor of the mTOR pathway.

An embodiment relates to any one of the aforementioned compounds,wherein the compound is a modulator of Pgp degradation, drug efflux, ordrug resistance.

An embodiment relates to a pharmaceutical composition comprising any oneor combination of the aforementioned compounds, and a pharmaceuticallyacceptable carrier.

Another embodiment relates to a method of inhibiting CK1 activity,comprising contacting CK1, CK1γ1, CK1γ2, or CK1γ3 with any one of theaforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of inhibiting CK2 activity,comprising contacting CK2 with any one of the aforementioned compoundsor pharmaceutical compositions.

Another embodiment relates to a method of treating or preventing acondition associated with aberrant CK1, CK1γ1, CK1γ2, or CK1γ3 activity,comprising administering to a mammal in need thereof a therapeuticallyeffective amount of any one of the aforementioned compounds orpharmaceutical compositions.

Another embodiment relates to a method of treating or preventing acondition associated with aberrant CK2 activity, comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of any one of the aforementioned compounds or pharmaceuticalcompositions.

Another embodiment relates to a method of treating cancer, comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of any one of the aforementioned compounds or pharmaceuticalcompositions. In one embodiment the cancer is a cancer of a systemselected from the group consisting of the hematopoietic system, immunesystem, endocrine system, pulmonary system, gastrointestinal system,musculoskeletal system, reproductive system, central nervous system, andurologic system. In one embodiment the cancer is located in the mammal'smyeloid tissues, lymphoid tissues, pancreatic tissues, thyroid tissues,lung tissues, colon tissues, rectal tissues, anal tissues, livertissues, skin, bone, ovarian tissues, uterine tissues, cervical tissues,breast, prostate, testicular tissues, brain, brainstem, meningealtissues, kidney or bladder. In one embodiment the cancer is selectedfrom the group consisting of breast cancer, colon cancer, multiplemyeloma, prostate cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma,leukemia, hematologic malignancy, renal cell carcinoma, renal cancer,malignant melanoma, pancreatic cancer, lung cancer, colorectalcarcinoma, brain cancer, head and neck cancer, bladder cancer, thyroidcancer, ovarian cancer, cervical cancer, and myelodysplastic syndrome.

Another embodiment relates to a method of treating leukemia or otherhematologic malignancies, comprising administering to a mammal in needthereof a therapeutically effective amount of any one of theaforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of treating Alzheimer's disease,comprising administering to a mammal in need thereof a therapeuticallyeffective amount of any one of the aforementioned compounds orpharmaceutical compositions.

Another embodiment relates to a method of treating a Wnt-dependentdisease, comprising administering to a mammal in need thereof atherapeutically effective amount of any one of the aforementionedcompounds or pharmaceutical compositions.

Another embodiment relates to a method of treating a TGFβ-dependentdisease, comprising administering to a mammal in need thereof atherapeutically effective amount of any one of the aforementionedcompounds or pharmaceutical compositions.

Another embodiment relates to a method of treating a JAK/STAT-dependentdisease, comprising administering to a mammal in need thereof atherapeutically effective amount of any one of the aforementionedcompounds or pharmaceutical compositions.

Another embodiment relates to a method of treating an mTOR-dependentdisease, comprising administering to a mammal in need thereof atherapeutically effective amount of any one of the aforementionedcompounds or pharmaceutical compositions.

Another embodiment relates to a method of treating or preventinginflammation, inflammatory diseases (e.g., osteoarthritis and rheumatoidarthritis), neurological conditions (e.g., Alzheimer's disease) andneurodegeneration, comprising administering to a mammal in need thereofa therapeutically effective amount of any one of the aforementionedcompounds or pharmaceutical compositions.

Another embodiment relates to a method of treating or preventingbone-related diseases and conditions, including osteoporosis and boneformation, or facilitating bone restoration, comprising administering toa mammal in need thereof a therapeutically effective amount of any oneof the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of treating or preventinghypoglycemia, metabolic syndrome and diabetes, comprising administeringto a mammal in need thereof a therapeutically effective amount of anyone of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of influencing apoptosis (e.g.,increasing the rate of apoptosis in cancerous cells), comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of any one of the aforementioned compounds or pharmaceuticalcompositions.

Another embodiment relates to a method of treating or preventingaberrant embryonic development, comprising administering to a mammal inneed thereof a therapeutically effective amount of any one of theaforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of inhibiting PIM activity,comprising contacting PIM1, PIM2 or PIM3 with any one of theaforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method for treating or preventing acondition associated with aberrant PIM activity, comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of any one of the aforementioned compounds or pharmaceuticalcompositions.

Another embodiment relates to a method of modulating Pgp degradationand/or drug efflux activity, comprising contacting a cell with any oneof the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method for treating a malignancy basedupon modulation of Pgp, comprising administering to a mammal in needthereof a therapeutically effective amount of any one of theaforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method for treating a malignancy basedupon modulation of Pgp, comprising administering to a mammal in needthereof a therapeutically effective amount of any one of theaforementioned compounds or pharmaceutical compositions, in conjunctionwith another drug, compound, or material, to abrogate resistance to thedrug, compound, or material.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the relative activity of CK1γ1(h) as a function of theconcentration of compound 4981.

FIG. 2 depicts the relative activity of CK1γ2(h) as a function of theconcentration of compound 4981.

FIG. 3 depicts the relative activity of CK1γ3(h) as a function of theconcentration of compound 4981.

FIG. 4 depicts the relative activity of CK1δ(h) as a function of theconcentration of compound 4981.

FIG. 5 depicts the relative activity of CK1(y) as a function of theconcentration of compound 4981.

FIG. 6 depicts the relative activity of CK1γ1(h) as a function of theconcentration of compound 4993.

FIG. 7 depicts the relative activity of CK1γ2(h) as a function of theconcentration of compound 4993.

FIG. 8 depicts the relative activity of CK1γ3(h) as a function of theconcentration of compound 4993.

FIG. 9 depicts the relative activity of CK1δ(h) as a function of theconcentration of compound 4993.

FIG. 10 depicts the relative activity of CK1(y) as a function of theconcentration of compound 4993.

FIG. 11 depicts the relative activity of CK1γ1(h) as a function of theconcentration of compound 4991.

FIG. 12 depicts the relative activity of CK1γ2(h) as a function of theconcentration of compound 4991.

FIG. 13 depicts the relative activity of CK1γ3(h) as a function of theconcentration of compound 4991.

FIG. 14 depicts the relative activity of CK1δ(h) as a function of theconcentration of compound 4991.

FIG. 15 depicts the relative activity of CK1(y) as a function of theconcentration of compound 4991.

FIG. 16 depicts the relative activity of CK1γ1(h) as a function of theconcentration of compound 4999.

FIG. 17 depicts the relative activity of CK1γ2(h) as a function of theconcentration of compound 4999.

FIG. 18 depicts the relative activity of CK1γ3(h) as a function of theconcentration of compound 4999.

FIG. 19 depicts the relative activity of CK1δ(h) as a function of theconcentration of compound 4999.

FIG. 20 depicts the relative activity of CK1(y) as a function of theconcentration of compound 4999.

FIG. 21 depicts the relative activity of CK1γ1(h) as a function of theconcentration of compound 4985.

FIG. 22 depicts the relative activity of CK1γ2(h) as a function of theconcentration of compound 4985.

FIG. 23 depicts the relative activity of CK1γ3(h) as a function of theconcentration of compound 4985.

FIG. 24 depicts the relative activity of CK1δ(h) as a function of theconcentration of compound 4985.

FIG. 25 depicts the relative activity of CK1(y) as a function of theconcentration of compound 4985.

FIG. 26 depicts the relative activity of CK1γ1(h) as a function of theconcentration of compound 4992.

FIG. 27 depicts the relative activity of CK1γ2(h) as a function of theconcentration of compound 4992.

FIG. 28 depicts the relative activity of CK1γ3(h) as a function of theconcentration of compound 4992.

FIG. 29 depicts the relative activity of CK1δ(h) as a function of theconcentration of compound 4992.

FIG. 30 depicts the relative activity of CK1(y) as a function of theconcentration of compound 4992.

FIG. 31 depicts the relative activity of CK1γ1(h) as a function of theconcentration of compound 4996.

FIG. 32 depicts the relative activity of CK1γ2(h) as a function of theconcentration of compound 4996.

FIG. 33 depicts the relative activity of CK1γ3(h) as a function of theconcentration of compound 4996.

FIG. 34 depicts the relative activity of CK1δ(h) as a function of theconcentration of compound 4996.

FIG. 35 depicts the relative activity of CK1(y) as a function of theconcentration of compound 4996.

FIG. 36 depicts the relative activity of CK1γ1(h) as a function of theconcentration of compound 5000.

FIG. 37 depicts the relative activity of CK1γ2(h) as a function of theconcentration of compound 5000.

FIG. 38 depicts the relative activity of CK1γ3(h) as a function of theconcentration of compound 5000.

FIG. 39 depicts the relative activity of CK1δ(h) as a function of theconcentration of compound 5000.

FIG. 40 depicts the relative activity of CK1(y) as a function of theconcentration of compound 5000.

FIG. 41 depicts the dose-response curve and EC₅₀ of gemcitabine againstPC-3 cells, which data served as an experimental control.

FIG. 42 depicts the dose-response curve and EC₅₀ of gemcitabine againstOVCAR-3 cells, which data served as an experimental control.

FIG. 43 depicts the dose-response curve and EC₅₀ of gemcitabine againstLNCaP cells, which data served as an experimental control.

FIG. 44 depicts the dose-response curve and EC₅₀ of gemcitabine againstJurkat cells, which data served as an experimental control.

FIG. 45 depicts the dose-response curve and EC₅₀ of gemcitabine againstMDA-MB-468 cells, which data served as an experimental control.

FIG. 46 depicts the dose-response curve and IC₅₀ of gemcitabine againstHCT116 cells, which data served as an experimental control.

FIG. 47 depicts the dose-response curve and IC₅₀ of gemcitabine againstA549 cells, which data served as an experimental control.

FIG. 48 depicts the dose-response curve and IC₅₀ of gemcitabine againstDU145 cells, which data served as an experimental control.

FIG. 49 depicts the dose-response curve and IC₅₀ of sorafenib againstHC1954 cells, which data served as an experimental control.

FIG. 50 depicts the dose-response curve and EC₅₀ of sorafenib againstCaco-2 cells, which data served as an experimental control.

FIG. 51 depicts the dose response curve and IC₅₀ of compound 4991against OVCAR-3 cells compared to cisplatin.

FIG. 52 depicts the dose response curve and IC₅₀ of compound 4991against OVCAR-8 cells compared to cisplatin.

FIG. 53 depicts the dose response curve and IC₅₀ of compound 4991against SK-OV-3 cells compared to cisplatin.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The definitions of terms used herein are meant to incorporate thepresent state-of-the-art definitions recognized for each term in thechemical and pharmaceutical fields. Where appropriate, illustration isprovided. The definitions apply to the terms as they are used throughoutthis specification, unless otherwise limited in specific instances,either individually or as part of a larger group.

Where stereochemistry is not specifically indicated, all stereoisomersof the inventive compounds are included within the scope of theinvention, as pure compounds as well as mixtures thereof. Unlessotherwise indicated, individual enantiomers, diastereomers, geometricalisomers, and combinations and mixtures thereof are all encompassed bythe present invention. Polymorphic crystalline forms and solvates arealso encompassed within the scope of this invention.

As used herein, the term “isolated” in connection with a compound of thepresent invention means the compound is not in a cell or organism andthe compound is separated from some or all of the components thattypically accompany it in nature.

As used herein, the term “pure” in connection with an isolated sample ofa compound of the present invention means the isolated sample containsat least 60% by weight of the compound. Preferably, the isolated samplecontains at least 70% by weight of the compound. More preferably, theisolated sample contains at least 80% by weight of the compound. Evenmore preferably, the isolated sample contains at least 90% by weight ofthe compound. Most preferably, the isolated sample contains at least 95%by weight of the compound. The purity of an isolated sample of acompound of the present invention may be assessed by a number of methodsor a combination of them; e.g., thin-layer, preparative or flashchromatography, mass spectrometry, HPLC, NMR analysis, and the like.

The term “heteroatom” is art-recognized and refers to an atom of anyelement other than carbon or hydrogen. Illustrative heteroatoms includeboron, nitrogen, oxygen, phosphorus, sulfur and selenium.

The term “alkyl” is art-recognized, and includes saturated aliphaticgroups, including straight-chain alkyl groups, branched-chain alkylgroups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkylgroups, and cycloalkyl substituted alkyl groups. In certain embodiments,a straight chain or branched chain alkyl has about 30 or fewer carbonatoms in its backbone (e.g., C₁-C₃₀ for straight chain, C₃-C₃₀ forbranched chain), and alternatively, about 20 or fewer. Likewise,cycloalkyls have from about 3 to about 10 carbon atoms in their ringstructure, and alternatively about 5, 6 or 7 carbons in the ringstructure.

Unless the number of carbons is otherwise specified, “lower alkyl”refers to an alkyl group, as defined above, but having from one to aboutten carbons, alternatively from one to about six carbon atoms in itsbackbone structure. Likewise, “lower alkenyl” and “lower alkynyl” havesimilar chain lengths.

The term “aralkyl” is art-recognized and refers to an alkyl groupsubstituted with an aryl group (e.g., an aromatic or heteroaromaticgroup).

The terms “alkenyl” and “alkynyl” are art-recognized and refer tounsaturated aliphatic groups analogous in length and possiblesubstitution to the alkyls described above, but that contain at leastone double or triple bond respectively.

The term “aryl” is art-recognized and refers to 5-, 6- and 7-memberedsingle-ring aromatic groups that may include from zero to fourheteroatoms, for example, benzene, naphthalene, anthracene, pyrene,pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole,pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.Those aryl groups having heteroatoms in the ring structure may also bereferred to as “aryl heterocycles” or “heteroaromatics.” The aromaticring may be substituted at one or more ring positions with suchsubstituents as described above, for example, halogen, azide, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro,sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester,heterocyclyl, aromatic or heteroaromatic moieties, —CF₃, —CN, or thelike. The term “aryl” also includes polycyclic ring systems having twoor more cyclic rings in which two or more carbons are common to twoadjoining rings (the rings are “fused rings”) wherein at least one ofthe rings is aromatic, e.g., the other cyclic rings may be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.

The terms ortho, meta and para are art-recognized and refer to 1,2-,1,3- and 1,4-disubstituted benzenes, respectively. For example, thenames 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The terms “heterocyclyl”, “heteroaryl”, or “heterocyclic group” areart-recognized and refer to 3- to about 10-membered ring structures,alternatively 3- to about 7-membered rings, whose ring structuresinclude one to four heteroatoms. Heterocycles may also be polycycles.Heterocyclyl groups include, for example, thiophene, thianthrene, furan,pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole,imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,phenanthridine, acridine, pyrimidine, phenanthroline, phenazine,phenarsazine, phenothiazine, piperonyl, furazan, phenoxazine,pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine,morpholine, lactones, lactams such as azetidinones and pyrrolidinones,sultams, sultones, and the like. The heterocyclic ring may besubstituted at one or more positions with such substituents as describedabove, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido,phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio,sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic orheteroaromatic moiety, —CF₃, —CN, or the like.

The term “optionally substituted” refers to a chemical group, such asalkyl, cycloalkyl aryl, and the like, wherein one or more hydrogen maybe replaced with a substituent as described herein, including but notlimited to halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic orheteroaromatic moieties, —CF₃, —CN, or the like.

The terms “polycyclyl” or “polycyclic group” are art-recognized andrefer to two or more rings (e.g., cycloalkyls, cycloalkenyls,cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbonsare common to two adjoining rings, e.g., the rings are “fused rings”.Rings that are joined through non-adjacent atoms are termed “bridged”rings. Each of the rings of the polycycle may be substituted with suchsubstituents as described above, as for example, halogen, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro,sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, aheterocyclyl, an aromatic or heteroaromatic moiety, —CF₃, —CN, or thelike.

The term “carbocycle” is art-recognized and refers to an aromatic ornon-aromatic ring in which each atom of the ring is carbon.

The term “nitro” is art-recognized and refers to —NO₂; the term“halogen” is art-recognized and refers to —F, —Cl, —Br or —I; the term“sulfhydryl” is art-recognized and refers to —SH; the term “hydroxyl”means —OH; and the term “sulfonyl” is art-recognized and refers to —SO₂⁻. “Halide” designates the corresponding anion of the halogens, and“pseudohalide” has the definition set forth on 560 of Advanced InorganicChemistry by Cotton and Wilkinson.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety that may berepresented by the general formulas:

wherein R50, R51 and R52 each independently represent a hydrogen, analkyl, an alkenyl, —(CH₂)_(m)—R61, or R50 and R51, taken together withthe N atom to which they are attached complete a heterocycle having from4 to 8 atoms in the ring structure; R61 represents an aryl, acycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zeroor an integer in the range of 1 to 8. In other embodiments, R50 and R51(and optionally R52) each independently represent a hydrogen, an alkyl,an alkenyl, or —(CH₂)_(m)—R61. Thus, the term “alkylamine” includes anamine group, as defined above, having a substituted or unsubstitutedalkyl attached thereto, i.e., at least one of R50 and R51 is an alkylgroup.

The term “acylamino” is art-recognized and refers to a moiety that maybe represented by the general formula:

wherein R50 is as defined above, and R54 represents a hydrogen, analkyl, an alkenyl or —(CH₂)_(m)—R61, where m and R61 are as definedabove.

The term “amido” is art recognized as an amino-substituted carbonyl andincludes a moiety that may be represented by the general formula:

wherein R50 and R51 are as defined above. Certain embodiments of theamide in the present invention will not include imides which may beunstable.

The term “alkylthio” refers to an alkyl group, as defined above, havinga sulfur radical attached thereto. In certain embodiments, the“alkylthio” moiety is represented by one of —S-alkyl, —S-alkenyl,—S-alkynyl, and —S—(CH₂)_(m)—R61, wherein m and R61 are defined above.Representative alkylthio groups include methylthio, ethyl thio, and thelike.

The term “carboxyl” is art recognized and includes such moieties as maybe represented by the general formulas:

wherein X50 is a bond or represents an oxygen or a sulfur, and R55 andR56 represents a hydrogen, an alkyl, an alkenyl, —(CH₂)_(m)—R61 or apharmaceutically acceptable salt, R56 represents a hydrogen, an alkyl,an alkenyl or —(CH₂)_(m)—R61, where m and R61 are defined above. WhereX50 is an oxygen and R55 or R56 is not hydrogen, the formula representsan “ester”. Where X50 is an oxygen, and R55 is as defined above, themoiety is referred to herein as a carboxyl group, and particularly whenR55 is a hydrogen, the formula represents a “carboxylic acid”. Where X50is an oxygen, and R56 is hydrogen, the formula represents a “formate”.In general, where the oxygen atom of the above formula is replaced bysulfur, the formula represents a “thiolcarbonyl” group. Where X50 is asulfur and R55 or R56 is not hydrogen, the formula represents a“thiolester.” Where X50 is a sulfur and R55 is hydrogen, the formularepresents a “thiolcarboxylic acid.” Where X50 is a sulfur and R56 ishydrogen, the formula represents a “thiolformate.” On the other hand,where X50 is a bond, and R55 is not hydrogen, the above formularepresents a “ketone” group. Where X50 is a bond, and R55 is hydrogen,the above formula represents an “aldehyde” group.

The term “carbamoyl” refers to —O(C═O)NRR′, where R and R′ areindependently H, aliphatic groups, aryl groups or heteroaryl groups.

The term “oxo” refers to a carbonyl oxygen (═O).

The terms “oxime” and “oxime ether” are art-recognized and refer tomoieties that may be represented by the general formula:

wherein R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,aralkyl, or —(CH₂)_(m)—R61. The moiety is an “oxime” when R is H; and itis an “oxime ether” when R is alkyl, cycloalkyl, alkenyl, alkynyl, aryl,aralkyl, or —(CH₂)_(m)—R61.

The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkylgroup, as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as may berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl,—O—(CH₂)_(m)—R61, where m and R61 are described above.

The term “sulfonate” is art recognized and refers to a moiety that maybe represented by the general formula:

in which R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

The term “sulfate” is art recognized and includes a moiety that may berepresented by the general formula:

in which R57 is as defined above.

The term “sulfonamido” is art recognized and includes a moiety that maybe represented by the general formula:

in which R50 and R56 are as defined above.

The term “sulfamoyl” is art-recognized and refers to a moiety that maybe represented by the general formula:

in which R50 and R51 are as defined above.

The term “sulfonyl” is art-recognized and refers to a moiety that may berepresented by the general formula:

in which R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl or heteroaryl.

The term “sulfoxido” is art-recognized and refers to a moiety that maybe represented by the general formula:

in which R58 is defined above.

The term “phosphoryl” is art-recognized and may in general berepresented by the formula:

wherein Q50 represents S or O, and R59 represents hydrogen, a loweralkyl or an aryl. When used to substitute, e.g., an alkyl, thephosphoryl group of the phosphorylalkyl may be represented by thegeneral formulas:

wherein Q50 and R59, each independently, are defined above, and Q51represents O, S or N. When Q50 is S, the phosphoryl moiety is a“phosphorothioate”.

The term “phosphoramidite” is art-recognized and may be represented inthe general formulas:

wherein Q51, R50, R51 and R59 are as defined above.

The term “phosphonamidite” is art-recognized and may be represented inthe general formulas:

wherein Q51, R50, R51 and R59 are as defined above, and R60 represents alower alkyl or an aryl.

Analogous substitutions may be made to alkenyl and alkynyl groups toproduce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls,amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls,carbonyl-substituted alkenyls or alkynyls.

The definition of each expression, e.g., alkyl, m, n, and the like, whenit occurs more than once in any structure, is intended to be independentof its definition elsewhere in the same structure.

The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized andrefer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl,and nonafluorobutanesulfonyl groups, respectively. The terms triflate,tosylate, mesylate, and nonaflate are art-recognized and refer totrifluoromethanesulfonate ester, p-toluenesulfonate ester,methanesulfonate ester, and nonafluorobutanesulfonate ester functionalgroups and molecules that contain said groups, respectively.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl,ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,p-toluenesulfonyl and methanesulfonyl, respectively. A morecomprehensive list of the abbreviations utilized by organic chemists ofordinary skill in the art appears in the first issue of each volume ofthe Journal of Organic Chemistry; this list is typically presented in atable entitled “Standard List of Abbreviations.”

Certain compounds contained in compositions of the present invention mayexist in particular geometric or stereoisomeric forms. In addition,polymers of the present invention may also be optically active. Thepresent invention contemplates all such compounds, including cis- andtrans-isomers, E- and Z-isomers, R- and S-enantiomers, diastereomers,(D)-isomers, (L)-isomers, the racemic mixtures thereof, and othermixtures thereof, as falling within the scope of the invention.Additional asymmetric carbon atoms may be present in a substituent suchas an alkyl group. All such isomers, as well as mixtures thereof, areintended to be included in this invention.

If, for instance, a particular enantiomer of compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivation with a chiral auxiliary, where the resulting diastereomericmixture is separated and the auxiliary group cleaved to provide the puredesired enantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

It will be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction.

The term “substituted” is also contemplated to include all permissiblesubstituents of organic compounds. In a broad aspect, the permissiblesubstituents include acyclic and cyclic, branched and unbranched,carbocyclic and heterocyclic, aromatic and nonaromatic substituents oforganic compounds. Illustrative substituents include, for example, thosedescribed herein above. The permissible substituents may be one or moreand the same or different for appropriate organic compounds. Forpurposes of this invention, the heteroatoms such as nitrogen may havehydrogen substituents and/or any permissible substituents of organiccompounds described herein which satisfy the valences of theheteroatoms. This invention is not intended to be limited in any mannerby the permissible substituents of organic compounds.

The phrase “protecting group” as used herein means temporarysubstituents which protect a potentially reactive functional group fromundesired chemical transformations. Examples of such protecting groupsinclude esters of carboxylic acids, silyl ethers of alcohols, andacetals and ketals of aldehydes and ketones, respectively. Examples ofnitrogen protecting groups include an amide (—NRC(═O)R) or a urethane(—NRC(═O)OR), for example, as: a methyl amide (—NHC(═O)CH₃); a benzyloxyamide (—NHC(═O)OCH₂C₆H₅NHCbz); as a t-butoxy amide (—NHC(═O)OC(CH₃)₃,—NHBoc); a 2-biphenyl-2-propoxy amide (—NHC(═O)OC(CH₃)₂C₆H₄C₆H₅NHBoc),as a 9-fluorenylmethoxy amide (—NHFmoc), as a 6-nitroveratryloxy amide(—NHNvoc), as a 2-trimethylsilylethyloxy amide (—NHTeoc), as a2,2,2-trichloroethyloxy amide (—NHTroc), as an allyloxy amide(—NHAlloc), as a 2-(phenylsulfonyl)ethyloxy amide (—NHPsec); or, insuitable cases (e.g., cyclic amines), as a nitroxide radical. The fieldof protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P.G. M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: NewYork, 1991). Protected forms of the inventive compounds are includedwithin the scope of this invention.

The term “pharmaceutically acceptable salt” or “salt” refers to a saltof one or more compounds. Suitable pharmaceutically acceptable salts ofcompounds include acid addition salts, such as those formed with mineralacids such as hydrochloric acid and hydrobromic acid, and also thoseformed with organic acids such as maleic acid. For example, acidscommonly employed to form pharmaceutically acceptable salts includeinorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic,hydroiodic, sulfuric and phosphoric acid, as well as organic acids suchas para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic,maleic, besylic, fumaric, gluconic, glucuronic, formic, glutamic,methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic,para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and aceticacid, and related inorganic and organic acids. Such pharmaceuticallyacceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite,bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,propionate, decanoate, caprylate, acrylate, formate, isobutyrate,caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate,benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate and the like.

Where the compounds carry one or more acidic moieties, pharmaceuticallyacceptable salts may be formed by treatment of a solution of thecompound with a solution of a pharmaceutically acceptable base. Suitablebases for forming pharmaceutically acceptable salts with acidicfunctional groups include, but are not limited to, hydroxides andcarbonates of alkali metals such as sodium, potassium, and lithium;alkaline earth metal such as calcium and magnesium; and other metals,such as aluminum and zinc. Suitable bases also include ammonia, andorganic amines, such as unsubstituted or hydroxy-substituted mono-, di-,or trialkylamines; dicyclohexylamine; tributyl amine; pyridine;N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, ortris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, ortris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, ortris-(hydroxymethyl)methylamine, N,N-di alkyl-N-(hydroxy alkyl)-amines,such as N,N-dimethyl-N-(2-hydroxyethyl)amine, ortri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such asarginine, lysine, and the like.

Certain compounds of the invention and their salts may exist in morethan one crystalline form (i.e., polymorph); the present inventionincludes each of the crystal forms and mixtures thereof.

Certain compounds of the invention and their salts may also exist in theform of solvates, for example hydrates, and the present inventionincludes each solvate and mixtures thereof.

Certain compounds of the invention may contain one or more chiralcenters, and exist in different optically active forms. When compoundsof the invention contain one chiral center, the compounds exist in twoenantiomeric forms and the present invention includes both enantiomersand mixtures of enantiomers, such as racemic mixtures thereof. Theenantiomers may be resolved by methods known to those skilled in theart; for example, enantiomers may be resolved by formation ofdiastereoisomeric salts which may be separated, for example, bycrystallization; formation of diastereoisomeric derivatives or complexeswhich may be separated, for example, by crystallization, gas-liquid orliquid chromatography; selective reaction of one enantiomer with anenantiomer-specific reagent, for example, via enzymatic esterification;or gas-liquid or liquid chromatography in a chiral environment, forexample, on a chiral support; suitable include chiral supports (e.g.,silica with a bound chiral ligand) or in the presence of a chiralsolvent. Where the desired enantiomer is converted into another chemicalentity by one of the separation procedures described above, a furtherstep may be used to liberate the desired purified enantiomer.Alternatively, specific enantiomers may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting one enantiomer into the other by asymmetrictransformation.

When a compound of the invention contains more than one chiral center,it may exist in diastereoisomeric forms. The diastereoisomeric compoundsmay be separated by methods known to those skilled in the art (forexample, chromatography or crystallization) and the individualenantiomers may be separated as described above. The present inventionincludes the various diastereoisomers of compounds of the invention, andmixtures thereof. Compounds of the invention may exist in differenttautomeric forms or as different geometric isomers, and the presentinvention includes each tautomer and/or geometric isomer of compounds ofthe invention, and mixtures thereof. For example, any olefins present inthe compounds may exist as either the E- or Z-geometric isomers or amixture thereof unless stated otherwise. Compounds of the invention mayexist in zwitterionic form. The present invention includes eachzwitterionic form of compounds of the invention, and mixtures thereof.

As used herein the term “pro-drug” refers to an agent, which isconverted into the parent drug in vivo by some physiological chemicalprocess (e.g., a prodrug on being brought to the physiological pH isconverted to the desired drug form). Pro-drugs are often useful because,in some situations, they may be easier to administer than the parentdrug. They may, for instance, be bioavailable by oral administrationwhereas the parent drug is not. The prodrug may also have improvedsolubility in pharmacological compositions over the parent drug. Anexample, without limitation, of a pro-drug would be a compound of thepresent invention wherein it is administered as an ester (the“pro-drug”) to facilitate transmittal across a cell membrane where watersolubility is not beneficial, but then it is metabolically hydrolyzed tothe carboxylic acid once inside the cell where water solubility isbeneficial. Pro-drugs have many useful properties. For example, apro-drug may be more water soluble than the ultimate drug, therebyfacilitating intravenous administration of the drug. A pro-drug may alsohave a higher level of oral bioavailability than the ultimate drug.After administration, the prodrug is enzymatically or chemically cleavedto deliver the ultimate drug in the blood or tissue.

Exemplary pro-drugs release an amine of a compound of the inventionwherein the free hydrogen of an amine or alcohol is replaced by(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyl-oxymethyl,N—(C₁-C₆)alkoxycarbonylamino-methyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylactyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl wherein said α-aminoacyl moieties areindependently any of the naturally occurring L-amino acids found inproteins, —P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radicalresulting from detachment of the hydroxyl of the hemiacetal of acarbohydrate).

Other exemplary pro-drugs upon cleavage release a corresponding freeacid, and such hydrolyzable ester-forming residues of the compounds ofthis invention include but are not limited to carboxylic acidsubstituents (e.g., —(CH₂)C(O)OH or a moiety that contains a carboxylicacid) wherein the free hydrogen is replaced by (C₁-C₄)alkyl,(C₂-C₁₂)alkanoyloxymethyl, (C₄-C₉)1-(alkanoyloxy)ethyl,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)-alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

The term “subject” as used herein, refers to an animal, typically amammal or a human, that will be or has been the object of treatment,observation, and/or experiment. When the term is used in conjunctionwith administration of a compound or drug, then the subject has been theobject of treatment, observation, and/or administration of the compoundor drug.

The terms “co-administration” and “co-administering” refer to bothconcurrent administration (administration of two or more therapeuticagents at the same time) and time varied administration (administrationof one or more therapeutic agents at a time different from that of theadministration of an additional therapeutic agent or agents), as long asthe therapeutic agents are present in the patient to some extent at thesame time.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits abiological or medicinal response in a cell culture, tissue system,animal, or human that is being sought by a researcher, veterinarian,clinician, or physician, which includes alleviation of the symptoms ofthe disease, condition, or disorder being treated.

The term “composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productthat results, directly or indirectly, from combinations of the specifiedingredients in the specified amounts.

The term “pharmaceutically acceptable carrier” refers to a medium thatis used to prepare a desired dosage form of a compound. Apharmaceutically acceptable carrier can include one or more solvents,diluents, or other liquid vehicles; dispersion or suspension aids;surface active agents; isotonic agents; thickening or emulsifyingagents; preservatives; solid binders; lubricants; and the like.Remington's Pharmaceutical Sciences, Fifteenth Edition, E. W. Martin(Mack Publishing Co., Easton, Pa., 1975) and Handbook of PharmaceuticalExcipients, Third Edition, A. H. Kibbe ed. (American PharmaceuticalAssoc. 2000), disclose various carriers used in formulatingpharmaceutical compositions and known techniques for the preparationthereof.

Compounds

An aspect of the invention relates to a compound of formula 1:

or a pharmaceutically acceptable salt thereof, wherein independently foreach occurrence:W and X are independently oxygen or sulfur;Z¹, Z² and Z³ are independently C—R²⁰ or N, provided that at least oneof Z¹ and Z² is N;R¹ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl,heterocyclylalkyl, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷),—SO₂N(R⁶)(R⁷), and —[C(R⁴)₂]_(p)—R⁵;R² and R³ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶,—C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), —P(O)(OR⁶)(OR⁷); orR² and R³ are joined together to form an optionally substitutedheterocyclic ring;

R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl,halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl;

R⁵ is selected from the group consisting of aryl, heteroaryl,heterocyclyl, —N(R⁸)(R⁹), —N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R⁸)SO₂(R⁹),—CON(R⁸)(R⁹), —OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR^(S),—C(O)N(OH)(R⁸), —OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR⁸,—OP(O)(OR⁸)(OR⁸), —P(O)(OR⁸)(OR⁸) and —N(R⁸)P(O)(OR⁹)(OR⁹);

R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl;R⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl; or R⁶ and R⁷ are joined together to form aheterocyclic ring;R⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl;R⁹ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl; or R⁸ and R⁹ are joined together to form aheterocyclic ring;R²⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl,heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl,perfluoroalkyl, thio, cyano, hydroxy, methoxy, alkoxy, phenoxy, aryloxy,heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino,arylamino, heteroarylamino, amido, acylamino, sulfate, sulfonate,sulfonyl, sulfoxido, sulfonamido, sulfamoyl, —[C(R⁴)₂]_(p)—R⁵, NR¹⁴R¹⁵,OR¹⁶, O—[C(R⁴)₂]_(p)—R⁵, NR¹⁴—[C(R⁴)₂]_(p)—R⁵ and SR¹⁶;R¹⁴ and R¹⁵ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]—R⁵, —COR⁶,—C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —P(O)(OR⁶)(OR⁷);or R¹⁴ and R¹⁵ are joined together to form an optionally substitutedheterocyclic ring;R¹⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl,heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, and —C(O)N(R⁶)(R⁷); andp is 1, 2, 3, 4, 5, or 6;

wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkylmay be optionally substituted.

In one embodiment, W and X are oxygen.

In one embodiment, Z¹ and Z² are nitrogen; and Z³ is C—R²⁰.

In one embodiment, Z¹, Z² and Z³ are nitrogen.

In one embodiment, Z¹ is nitrogen; and Z² and Z³ are each C—R²⁰.

In one embodiment, Z² is nitrogen; and Z¹ and Z³ are each C—R²⁰.

In one embodiment, R¹ is hydrogen.

In one embodiment, R¹ is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, and —[C(R⁴)₂]_(p)—R⁵.

In one embodiment, W and X are oxygen, Z¹ and Z² are each nitrogen, Z³is C—R²⁰ and R¹ is hydrogen.

In one embodiment, R² and R³ are joined together to form an optionallysubstituted heterocyclic ring.

In one embodiment, the optionally substituted heterocyclic ring isselected from the group consisting of piperazinyl, homopiperizinyl,pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl,1,4-diazepan-5-onyl and quinolinyl.

In one embodiment, R² and R³ are independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶, —SO₂(R⁶),—C(O)N(R⁶)(R⁷), and —SO₂N(R⁶)(R⁷), wherein the alkyl, alkenyl, alkynyl,aryl, heteroaryl, and heterocyclyl may be optionally substituted.

In one embodiment, R² is —[C(R⁴)₂]_(p)—R⁵, and R³ is selected from thegroup consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), and—SO₂N(R⁶)(R⁷), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl,and heterocyclyl may be optionally substituted.

In one embodiment, R⁵ is aryl or heteroaryl, each of which may beoptionally substituted.

In one embodiment, R⁵ is —N(R⁸)(R⁹).

In one embodiment, R⁴ is hydrogen.

In one embodiment, R²⁰ is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, haloalkyl,trifluoromethyl, carboxyl, alkoxycarbonyl, acyl, nitro, amido,acylamino, sulfonamido, —[C(R⁴)₂]_(p)—R⁵; NR¹⁴R¹⁵, OR¹⁶, and SR¹⁶.

In one embodiment, R²⁰ is hydrogen.

An aspect of the invention relates to compound of formula 2:

or a pharmaceutically acceptable salt thereof, wherein independently foreach occurrence:R¹ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl,heterocyclylalkyl, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷),—SO₂N(R⁶)(R⁷), and —[C(R⁴)₂]_(p)—R⁵;R² and R³ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶,—C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷)—P(O)(OR⁶)(OR⁷); or R²and R³ are joined together to form an optionally substitutedheterocyclic ring;R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl,halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl;R⁵ is selected from the group consisting of aryl, heteroaryl,heterocyclyl, —N(R⁸)(R⁹), —N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R)SO₂(R⁹),—CON(R⁸)(R⁹), —OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR^(S),—C(O)N(OH)(R⁸), —OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR⁸,—OP(O)(OR⁸)(OR⁹), —P(O)(OR⁸)(OR⁹) and —N(R⁸)P(O)(OR⁹)(OR⁹);R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl;R⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl, or R⁶ and R⁷ are joined together to form aheterocyclic ring;R⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl;R⁹ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl; or R⁸ and R⁹ are joined together to form aheterocyclic ring;R²⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl,heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl,perfluoroalkyl, thio, cyano, hydroxy, methoxy, alkoxy, phenoxy, aryloxy,heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino,arylamino, heteroarylamino, amido, acylamino, sulfate, sulfonate,sulfonyl, sulfoxido, sulfonamido, sulfamoyl, —[C(R⁴)₂]_(p)—R⁵, NR¹⁴R¹⁵,OR¹⁶, and SR¹⁶;R¹⁴ and R¹⁵ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶,—C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —P(O)(OR⁶)(OR⁷);or R¹⁴ and R¹⁵ are joined together to form an optionally substitutedheterocyclic ring;R¹⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl,heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, and —C(O)N(R⁶)(R⁷); andp is 1, 2, 3, 4, 5, or 6;

wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkylmay be optionally substituted.

In one embodiment, R¹ is hydrogen.

In one embodiment, R²⁰ is selected from the group consisting ofhydrogen, alkyl, trifluoromethyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, —[C(R⁴)₂]_(p)—R⁵, NR¹⁴R¹⁵, OR¹⁶, and SR¹⁶.

In one embodiment, R²⁰ is hydrogen.

In one embodiment, R² and R³ are joined together to form an optionallysubstituted heterocyclic ring.

In one embodiment, R² and R³ are joined together to form an optionallysubstituted heterocyclic ring selected from the group consisting of:

wherein, independently for each occurrence:R¹⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl,heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR¹², —C(O)OR¹²,—SO₂(R¹²)—SO₂N(R¹²)(R¹³), —P(O)(OR¹²)(OR¹³);R¹² and R¹³ are selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, and heterocyclylalkyl; or R¹² and R¹³ are joined togetherto form a heterocyclic ring;R¹¹ is selected from the group consisting of alkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclyl, halo, haloalkyl, thio, cyano,hydroxyalkyl, alkoxy, alkylalkoxy, alkylthio, nitro, cyano,—N(R¹⁷)(R¹⁸), —N(R¹⁷)COR¹⁸, —N(R¹⁷)C(O)OR¹⁸, —N(R¹⁷)SO₂(R¹⁸),—CON(R¹⁷)(R¹⁸), —OC(O)N(R¹⁷)—(R¹⁸), —SO₂N(R¹⁷)(R¹⁸), —OC(O)OR¹⁷,—COOR¹⁷, —C(O)N(OH)(R¹⁷), —OS(O)₂OR¹⁷, —S(O)₂OR¹⁷, —S(O)₂R¹⁷, —OR¹⁷,—COR¹⁷, —OP(O)(OR¹⁷)(OR¹⁸), —P(O)(OR¹⁷)(OR¹⁸), —N(R¹⁷)P(O)(OR¹⁸)(OR¹⁸),and —[C(R⁴)₂]_(p)—R⁵;R¹⁷ and R¹⁸ selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, and heterocyclylalkyl; or R¹⁷ and R¹⁸ are joined togetherto form a heterocyclic ring; andn is 0, 1, 2, or 3;

wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkylmay be optionally substituted.

In one embodiment, R¹⁰ is selected from the group consisting ofhydrogen, alkyl, aryl, heteroaryl, heterocyclyl, —[C(R⁴)₂]_(p)—R⁵,—COR¹², —C(O)OR¹², and —SO₂(R¹²);

wherein any one of the aforementioned alkyl, aryl, heteroaryl, andheterocyclyl may be optionally substituted.

In one embodiment, n is 0.

In one embodiment, n is 1.

In one embodiment, R¹¹ is selected from the group consisting of alkyl,heterocyclyl, cyano, hydroxyalkyl, —N(R¹⁷)(R¹⁸), —CON(R¹⁷)(R¹⁸), and—[C(R⁴)₂]^(p)—R⁵;

wherein any of the aforementioned alkyl and heterocyclyl may beoptionally substituted.

In one embodiment, R² and R³ are joined together to form an optionallysubstituted heterocyclic ring of the formula:

In one embodiment, n is 0 or 1.

In one embodiment, R² and R³ are joined together to form an optionallysubstituted heterocyclic ring of the formula:

In one embodiment, R² and R³ are independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶, —SO₂(R⁶),—C(O)N(R⁶)(R⁷), and —SO₂N(R⁶)(R⁷), wherein the alkyl, alkenyl, alkynyl,aryl, heteroaryl, and heterocyclyl may be optionally substituted.

In one embodiment, R³ is —[C(R⁴)₂]_(p)—R⁵.

In one embodiment, R² is optionally substituted alkyl.

In one embodiment, R⁴ is hydrogen.

In one embodiment, R⁴ is hydroxy.

In one embodiment, R⁵ is aryl, heteroaryl, heterocyclyl, each of whichmay be optionally substituted.

In one embodiment, p is 1, 2 or 3.

In one embodiment, R⁵ is selected from the group consisting of—N(R⁸)(R⁹), —N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R⁸)SO₂(R⁹), —CON(R⁸)(R⁹),—OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR⁹, —C(O)N(OH)(R⁸),—OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR^(S), —OP(O)(OR⁸)(OR⁸),—P(O)(OR⁸)(OR⁸) and —N(R⁸)P(O)(OR⁹)(OR⁹).

In one embodiment, R⁵ is —N(R⁸)(R⁹).

An aspect of the invention relates to a compound, or a pharmaceuticallyacceptable salt thereof, selected from the group consisting of:

An aspect of the invention relates to a compound, or a pharmaceuticallyacceptable salt thereof, selected from the group consisting of:

Any one of the aforementioned compounds may exist as the E-geometricisomer, the Z-geometric isomer, or mixtures thereof. For example, in oneembodiment,

in the aforementioned structures represents the E-isomer of theparticular compound. In another embodiment,

represents the Z-isomer of the particular compound. In yet anotherembodiment,

represents a mixture of E and Z isomers of the particular compound.

In one embodiment, any one of the aforementioned compounds is aninhibitor of CK1γ1, CK1γ2, or CK1γ3.

In one embodiment, any one of the aforementioned compounds is aninhibitor of CK2.

In one embodiment, any one of the aforementioned compounds is aninhibitor of the Wnt pathway.

In one embodiment, any one of the aforementioned compounds is aninhibitor of the JAK/STAT pathway.

In one embodiment, any one of the aforementioned compounds is aninhibitor of the mTOR pathway.

In one embodiment, any one of the aforementioned compounds is a mediatorof Pgp degradation and/or drug efflux.

In one embodiment, any one of the aforementioned compounds is aninhibitor of the TGFβ pathway.

In some embodiments, the compound has an IC₅₀ of less than 5000 nM forCK1γ1, CK1γ2, or CK1γ3.

In some embodiments, the compound has an IC₅₀ of less than 1000 nM forCK1γ1, CK1γ2, or CK1γ3.

In some embodiments, the compound has an IC₅₀ of less than 500 nM forCK1γ1, CK1γ2, or CK1γ3.

In one embodiment, any one of the aforementioned compounds is aninhibitor of CK2.

In one embodiment, the compound has an IC₅₀ of less than 5000 nM forCK2.

In one embodiment, the compound has an IC₅₀ of less than 1000 nM forCK2.

In one embodiment, the compound has an IC₅₀ of less than 500 nM for CK2.

In one embodiment, any on of the aforementioned compounds is aninhibitor of PIM1, PIM2, or PIM3.

In one embodiment, the compound has an IC₅₀ of less than 5000 nM forPIM1, PIM2 or PIM3.

In one embodiment, the compound has an IC₅₀ of less than 1000 nM forPIM1, PIM2 or PIM3.

In one embodiment, the compound has an IC₅₀ of less than 500 nM forPIM1, PIM2 or PIM3.

General Synthetic Schemes

General synthetic schemes that were utilized to prepare compoundsdisclosed in this application are described below. For example,compounds of the invention may be prepared as shown in Scheme I:

Alternatively, the compounds of the invention can be made as shown inScheme II:

Yet another method of making the compounds disclosed herein is depictedin Scheme III:

PROPHETIC EMBODIMENTS

Certain compounds of the invention could be made in accordance with theabove schemes by reacting an amine (Reactant A) with the hydantoin core(Reactant B). Non-limiting prophetic examples of Reactant A and ReactantB are shown in Table 1 and Table 2, respectively.

TABLE 1 Reactant A Prophetic Examples. Reactant A #1 Structure

Molecular Weight 162.232 Molecular Formula C₁₀H₁₄N₂ Chemical name1-phenylpiperazine Reactant A #2 Structure

Molecular Weight 163.22 Molecular Formula C₉H₁₃N₃ Chemical name1-(pyridin-3-yl)piperazine Reactant A #3 Structure

Molecular Weight 164.208 Molecular Formula C₈H₁₂N₄ Chemical name5-(piperazin-1-yl)pyrimidine Reactant A #4 Structure

Molecular Weight 164.208 Molecular Formula C₈H₁₂N₄ Chemical name2-(piperazin-1-yl)pyrimidine Reactant A #5 Structure

Molecular Weight 205.256 Molecular Formula C₁₁H₁₅N₃O Chemical nameN-phenylpiperazine-1-carboxamide Reactant A #6 Structure

Molecular Weight 197.32 Molecular Formula C₁₁H₂₃N₃ Chemical name1-(1-ethylpiperidin-4-yl)piperazine Reactant A #7 Structure

Molecular Weight 177.246 Molecular Formula C₁₀H₁₅N₃ Chemical name1-(pyridin-4-yl)-1,4-diazepane Reactant A #8 Structure

Molecular Weight 217.267 Molecular Formula C₁₂H₁₅N₃O Chemical name2-(1,4-diazepan-1-yl)benzo[d]oxazole Reactant A #9 Structure

Molecular Weight 219.283 Molecular Formula C₁₂H₁₇N₃O Chemical nameN-phenyl-1,4-diazepane-1-carboxamide Reactant A #10 Structure

Molecular Weight 261.366 Molecular Formula C₁₄H₂₃N₅ Chemical name1-(6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4-yl)-1,4- diazepane Reactant A#11 Structure

Molecular Weight 130.231 Molecular Formula C₇H₁₈N₂ Chemical nameN1,N1-diethyl-N2-methylethane-1,2-diamine Reactant A #12 Structure

Molecular Weight 251.305 Molecular Formula C₁₁H₁₃N₃O₂S Chemical nameN-(2-aminoethyl)isoquinoline-5-sulfonamide Reactant A #13 Structure

Molecular Weight 164.204 Molecular Formula C₉H₁₂N₂O Chemical nameN-(2-aminoethyl)benzamide Reactant A #14 Structure

Molecular Weight 189.214 Molecular Formula C₁₀H₁₁N₃O Chemical name2-(2-aminoethyl)quinazolin-4(3H)-one Reactant A #15 Structure

Molecular Weight 190.242 Molecular Formula C₁₁H₁₄N₂O Chemical namephenyl(piperazin-1-yl)methanone Reactant A #16 Structure

Molecular Weight 226.295 Molecular Formula C₁₀H₁₄N₂O₂S Chemical name1-(phenylsulfonyl)piperazine Reactant A #17 Structure

Molecular Weight 216.279 Molecular Formula C₁₃H₁₆N₂O Chemical name(hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)(phenyl)methanone Reactant A#18 Structure

Molecular Weight 252.333 Molecular Formula C₁₂H₁₆N₂O₂S Chemical name2-(phenylsulfonyl)octahydropyrrolo[3,4-c]pyrrole Reactant A #19Structure

Molecular Weight 231.294 Molecular Formula C₁₃H₁₇N₃O Chemical nameN-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide Reactant A #20Structure

Molecular Weight 217.267 Molecular Formula C₁₂H₁₅N₃O Chemical nameN-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxamide Reactant A #21Structure

Molecular Weight 202.252 Molecular Formula C₁₂H₁₄N₂O Chemical namephenyl(2,6-diazaspiro[3.3]heptan-2-yl)methanone Reactant A #22 Structure

Molecular Weight 238.306 Molecular Formula C₁₁H₁₄N₂O₂S Chemical name2-(phenylsulfonyl)-2,6-diazaspiro[3.3]heptane

TABLE 2 Reactant B Prophetic Examples. Reactant B #1 Structure

Molecular Formula C₁₂H₁₁ClN₄O₃S Molecular Weight 326.759 Chemical name(Z)-5-((2-chloro-6-morpholinopyrimidin-4-yl)methylene)thiazolidine-2,4-dione Reactant B #2 Structure

Molecular Formula C₁₃H₁₄ClN₅O₂S Molecular Weight 339.801 Chemical name(Z)-5-((2-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione Reactant B #3 Structure

Molecular Formula C₁₆H₁₃ClN₄O₂S Molecular Weight 360.818 Chemical name(Z)-5-((6-(benzyl(methyl)amino)-2-chloropyrimidin-4-yl)methylene)thiazolidine-2,4-dione Reactant B #4 Structure

Molecular Formula C₁₁H₁₁ClN₄O₃S Molecular Weight 314.748 Chemical name(Z)-5-((2-chloro-6-((2- hydroxyethyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione Reactant B #5 Structure

Molecular Formula C₁₅H₁₁ClN₄O₂S Molecular Weight 346.791 Chemical name(Z)-5-((2-chloro-6-(methyl(phenyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione Reactant B #6 Structure

Molecular Formula C₁₃H₈ClN₃O₄S Molecular Weight 337.738 Chemical name(Z)-5-((2-chloro-6-(furan-2-ylmethoxy)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione Reactant B #7 Structure

Molecular Formula C₁₄H₈ClN₃O₃S Molecular Weight 333.75 Chemical name(Z)-5-((2-chloro-6-phenoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione Reactant B #8 Structure

Molecular Formula C₁₅H₁₀ClN₃O₃S Molecular Weight 347.776 Chemical name(Z)-5-((6-(benzyloxy)-2-chloropyrimidin-4-yl)methylene)thiazolidine-2,4-dione Reactant B #9 Structure

Molecular Formula C₁₁H₁₀ClN₃O₄S Molecular Weight 315.733 Chemical name(Z)-5-((2-chloro-6-(2-methoxyethoxy)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione Reactant B #10 Structure

Molecular Formula C₁₂H₁₃ClN₄O₃S Molecular Weight 328.775 Chemical name(Z)-5-((2-chloro-6-(2-(dimethylamino)ethoxy)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione Reactant B #11 Structure

Molecular Formula C₈H₄ClN₃O₂S Molecular Weight 241.654 Chemical name(Z)-5-((2-chloropyrimidin-4-yl)methylene) thiazolidine-2,4-dioneReactant B #12 Structure

Molecular Formula C₇H₃ClN₄O₂S Molecular Weight 242.642 Chemical name(Z)-5-((4-chloro-1,3,5-triazin-2-yl) methylene)thiazolidine-2,4-dione

Additional prophetic embodiments of the invention that may be made inaccordance with the above reaction schemes using Reactants A and B arelisted in Table 3. The geometric isomers listed in Table 3 are believedto reflect the actual geometry of the prophetic compounds if they wereto be made; however, final structural assignments may only be made ifthe compounds are synthesized and subjected to appropriate 2D NMRexperiments. Further, although the compounds are listed as the “Z”geometric isomer, both the E and Z geometric isomers and mixturesthereof are contemplated.

TABLE 3 Additional prophetic embodiments of the invention. Mol. ReactantNo. Chemical Name Formula Weight A B 1(Z)-5-((6-morpholino-2-(4-phenylpiperazin-1- C₂₂H₂₄N₆O₃S 452.529 1 1yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 2(Z)-5-((6-morpholino-2-(4-(pyridin-3-yl)piperazin-1- C₂₁H₂₃N₇O₃S 453.5172 1 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 3(Z)-5-((6-morpholino-2-(4-(pyrimidin-5-yl)piperazin- C₂₀H₂₂N₈O₃S 454.5053 1 1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 4(Z)-5-((6-morpholino-2-(4-(pyrimidin-2-yl)piperazin- C₂₀H₂₂N₈O₃S 454.5054 1 1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 5(Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₃H₂₅N₇O₄S 495.5545 1 morpholinopyrimidin-2-yl)-N-phenylpiperazine-1- carboxamide 6(Z)-5-((2-(4-(1-ethylpiperidin-4-yl)piperazin-1-yl)-6- C₂₃H₃₃N₇O₃S487.618 6 1 morpholinopyrimidin-4-yl)methylene)thiazolidine-2,4- dione 7(Z)-5-((6-morpholino-2-(4-(pyridin-4-yl)-1,4-diazepan- C₂₂H₂₅N₇O₃S467.544 7 1 1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 8(Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₂₄H₂₅N₇O₄S507.565 8 1 6-morpholinopyrimidin-4-yl)methylene)thiazolidine- 2,4-dione9 (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₄H₂₇N₇O₄S509.581 9 1 morpholinopyrimidin-2-yl)-N-phenyl-1,4-diazepane-1-carboxamide 10 (Z)-5-((2-(4-(6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4-C₂₆H₃₃N₉O₃S 551.664 10 1 yl)-1,4-diazepan-1-yl)-6-morpholinopyrimidin-4-yl)methylene)thiazolidine-2,4-dione 11(Z)-5-((2-((2-(diethylamino)ethyl)(methyl)amino)-6- C₁₉H₂₈N₆O₃S 420.52911 1 morpholinopyrimidin-4-yl)methylene)thiazolidine-2,4- dione 12(Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₃H₂₃N₇O₅S₂541.603 12 1 6-morpholinopyrimidin-2-yl)amino)ethyl)isoquinoline-5-sulfonamide 13 (Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)-C₂₁H₂₂N₆O₄S 454.502 13 16-morpholinopyrimidin-2-yl)amino)ethyl)benzamide 14(Z)-5-((6-morpholino-2-((2-(4-oxo-3,4- C₂₂H₂₁N₇O₄S 479.512 14 1dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 15(Z)-5-((2-(4-benzoylpiperazin-1-yl)-6- C₂₃H₂₄N₆O₄S 480.539 15 1morpholinopyrimidin-4-yl)methylene)thiazolidine-2,4- dione 16(Z)-5-((6-morpholino-2-(4-(phenylsulfonyl)piperazin- C₂₂H₂₄N₆O₅S₂516.593 16 1 1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 17(Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₅H₂₆N₆O₄S 506.57717 1 2(1H)-yl)-6-morpholinopyrimidin-4-yl)methylene)thiazolidine-2,4-dione 18 (Z)-5-((6-morpholino-2-(5-C₂₄H₂₆N₆O₅S₂ 542.63 18 1(phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 19(Z)-5-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₅H₂₇N₇O₄S 521.59119 1 morpholinopyrimidin-2-yl)-N-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 20(Z)-6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₄H₂₅N₇O₄S 507.56520 1 morpholinopyrimidin-2-yl)-N-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxamide 21(Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₄H₂₄N₆O₄S 492.5521 1 6-morpholinopyrimidin-4-yl)methylene)thiazolidine- 2,4-dione 22(Z)-5-((6-morpholino-2-(6-(phenylsulfonyl)-2,6- C₂₃H₂₄N₆O₅S₂ 528.604 221 diazaspiro[3.3]heptan-2-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 23(Z)-5-((6-(4-methylpiperazin-1-yl)-2-(4- C₂₃H₂₇N₇O₂S 465.571 1 2phenylpiperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 24(Z)-5-((6-(4-methylpiperazin-1-yl)-2-(4-(pyridin-3- C₂₂H₂₆N₈O₂S 466.5592 2 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione25 (Z)-5-((6-(4-methylpiperazin-1-yl)-2-(4-(pyrimidin-5- C₂₁H₂₅N₉O₂S467.547 3 2 yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 26(Z)-5-((6-(4-methylpiperazin-1-yl)-2-(4-(pyrimidin-2- C₂₁H₂₅N₉O₂S467.547 4 2 yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 27(Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-(4- C₂₄H₂₈N₈O₃S508.596 5 2 methylpiperazin-1-yl)pyrimidin-2-yl)-N-phenylpiperazine-1-carboxamide 28(Z)-5-((2-(4-(1-ethylpiperidin-4-yl)piperazin-1-yl)-6- C₂₄H₃₆N₈O₂S500.66 6 2 (4-methylpiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 29(Z)-5-((6-(4-methylpiperazin-1-yl)-2-(4-(pyridin-4-yl)- C₂₃H₂₈N₈O₂S480.586 7 2 1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 30(Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₂₅H₂₈N₈O₃S520.607 8 2 6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 31(Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-(4- C₂₅H₃₀N₈O₃S522.623 9 2 methylpiperazin-1-yl)pyrimidin-2-yl)-N-phenyl-1,4-diazepane-1-carboxamide 32(Z)-5-((2-(4-(6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4- C₂₇H₃₆N₁₀O₂S564.706 10 2 yl)-1,4-diazepan-1-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 33(Z)-5-((2-((2-(diethylamino)ethyl)(methyl)amino)-6- C₂₀H₃₁N₇O₂S 433.57111 2 (4-methylpiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 34(Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₄H₂₆N₈O₄S₂554.644 12 2 6-(4-methylpiperazin-1-yl)pyrimidin-2-yl)amino)ethyl)isoquinoline-5-sulfonamide 35(Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₂H₂₅N₇O₃S467.544 13 2 6-(4-methylpiperazin-1-yl)pyrimidin-2-yl)amino)ethyl)benzamide 36(Z)-5-((6-(4-methylpiperazin-1-yl)-2-((2-(4-oxo-3,4- C₂₃H₂₄N₈O₃S 492.55314 2 dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 37(Z)-5-((2-(4-benzoylpiperazin-1-yl)-6-(4- C₂₄H₂₇N₇O₃S 493.581 15 2methylpiperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 38(Z)-5-((6-(4-methylpiperazin-1-yl)-2-(4- C₂₃H₂₇N₇O₄S₂ 529.635 16 2(phenylsulfonyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 39(Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₆H₂₉N₇O₃S 519.61917 2 2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 40(Z)-5-((6-(4-methylpiperazin-1-yl)-2-(5- C₂₅H₂₉N₇O₄S₂ 555.672 18 2(phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 41(Z)-5-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-(4- C₂₆H₃₀N₈O₃S534.633 19 2 methylpiperazin-1-yl)pyrimidin-2-yl)-N-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 42(Z)-6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-(4- C₂₅H₂₈N₈O₃S520.607 20 2 methylpiperazin-1-yl)pyrimidin-2-yl)-N-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxamide 43(Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₅H₂₇N₇O₃S505.592 21 2 6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 44(Z)-5-((6-(4-methylpiperazin-1-yl)-2-(6- C₂₄H₂₇N₇O₄S₂ 541.646 22 2(phenylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 45(Z)-5-((6-(benzyl(methyl)amino)-2-(4- C₂₆H₂₆N₆O₂S 486.589 1 3phenylpiperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 46(Z)-5-((6-(benzyl(methyl)amino)-2-(4-(pyridin-3- C₂₅H₂₅N₇O₂S 487.577 2 3yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 47(Z)-5-((6-(benzyl(methyl)amino)-2-(4-(pyrimidin-5- C₂₄H₂₄N₈O₂S 488.565 33 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 48(Z)-5-((6-(benzyl(methyl)amino)-2-(4-(pyrimidin-2- C₂₄H₂₄N₈O₂S 488.565 43 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 49(Z)-4-(4-(benzyl(methyl)amino)-6-((2,4- C₂₇H₂₇N₇O₃S 529.613 5 3dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-N-phenylpiperazine-1-carboxamide 50(Z)-5-((6-(benzyl(methyl)amino)-2-(4-(1- C₂₇H₃₅N₇O₂S 521.678 6 3ethylpiperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 51(Z)-5-((6-(benzyl(methyl)amino)-2-(4-(pyridin-4-yl)- C₂₆H₂₇N₇O₂ 501.6037 3 1,4-diazepan-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione52 (Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₂₈H₂₇N₇O₃S541.624 8 3 6-(benzyl(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 53(Z)-4-(4-(benzyl(methyl)amino)-6-((2,4- C₂₈H₂₉N₇O₃S 543.64 9 3dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-N-phenyl-1,4-diazepane-1-carboxamide 54(Z)-5-((6-(benzyl(methyl)amino)-2-(4-(6-methyl-2- C₃₀H₃₅N₉O₂S 585.723 103 (pyrrolidin-1-yl)pyrimidin-4-yl)-1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 55(Z)-5-((6-(benzyl(methyl)amino)-2-((2- C₂₃H₃₀N₆O₂S 454.588 11 3(diethylamino)ethyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 56(Z)-N-(2-((4-(benzyl(methyl)amino)-6-((2,4- C₂₇H₂₅N₇O₄S₂ 575.662 12 3dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)amino)ethyl)isoquinoline-5-sulfonamide 57(Z)-N-(2-((4-(benzyl(methyl)amino)-6-((2,4- C₂₅H₂₄N₆O₃S 488.561 13 3dioxothiazolidin-5-ylidene)methyl)pyrimidin-2- yl)amino)ethyl)benzamide58 (Z)-5-((6-(benzyl(methyl)amino)-2-((2-(4-oxo-3,4- C₂₆H₂₃N₇O₃S 513.57114 3 dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 59(Z)-5-((2-(4-benzoylpiperazin-1-yl)-6- C₂₇H₂₆N₆O₃S 514.599 15 3(benzyl(methyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 60(Z)-5-((6-(benzyl(methyl)amino)-2-(4- C₂₆H₂₆N₆O₄S₂ 550.652 16 3(phenylsulfonyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 61(Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₉H₂₈N₆O₃S 540.63617 3 2(1H)-yl)-6-(benzyl(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 62(Z)-5-((6-(benzyl(methyl)amino)-2-(5- C₂₈H₂₈N₆O₄S₂ 576.69 18 3(phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 63(Z)-5-(4-(benzyl(methyl)amino)-6-((2,4- C₂₉H₂₉N₇O₃S 555.651 19 3dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-N-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 64(Z)-6-(4-(benzyl(methyl)amino)-6-((2,4- C₂₈H₂₇N₇O₃S 541.624 20 3dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-N-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxamide 65(Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₈H₂₆N₆O₃S526.609 21 3 6-(benzyl(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 66(Z)-5-((6-(benzyl(methyl)amino)-2-(6- C₂₇H₂₆N₆O₄S₂ 562.663 22 3(phenylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 67(Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-(4- C₂₁H₂₄N₆O₃S 440.519 1 4phenylpiperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 68(Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-(4- C₂₀H₂₃N₇O₃S 441.507 2 4(pyridin-3-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 69(Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-(4- C₁₉H₂₂N₈O₃S 442.495 3 4(pyrimidin-5-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 70(Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-(4- C₁₉H₂₂N₈O₃S 442.495 4 4(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 71(Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₂H₂₅N₇O₄S 483.5435 4 ((2-hydroxyethyl)(methyl)amino)pyrimidin-2-yl)-N-phenylpiperazine-1-carboxamide 72(Z)-5-((2-(4-(1-ethylpiperidin-4-yl)piperazin-1-yl)-6- C₂₂H₃₃N₇O₃S475.608 6 4 ((2-hydroxyethyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 73(Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-(4- C₂₁H₂₅N₇O₃S 455.533 7 4(pyridin-4-yl)-1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 74(Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₂₃H₂₅N₇O₄S495.554 8 4 6-((2-hydroxyethyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 75(Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₃H₂₇N₇O₄S 497.579 4 ((2-hydroxyethyl)(methyl)amino)pyrimidin-2-yl)-N-phenyl-1,4-diazepane-1-carboxamide 76(Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-(4-(6- C₂₅H₃₃N₉O₃S 539.65310 4 methyl-2-(pyrrolidin-1-yl)pyrimidin-4-yl)-1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine- 2,4-dione 77(Z)-5-((2-((2-(diethylamino)ethyl)(methyl)amino)-6- C₁₈H₂₈N₆O₃S 408.51811 4 ((2-hydroxyethyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 78(Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₂H₂₃N₇O₅S₂529.592 12 4 6-((2-hydroxyethyl)(methyl)amino)pyrimidin-2-yl)amino)ethyl)isoquinoline-5-sulfonamide 79(Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₀H₂₂N₆O₄S442.491 13 4 6-((2-hydroxyethyl)(methyl)amino)pyrimidin-2-yl)amino)ethyl)benzamide 80(Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-((2-(4- C₂₁H₂₁N₇O₄S 467.50114 4 oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-4-yl)methylene)thiazolidine- 2,4-dione 81(Z)-5-((2-(4-benzoylpiperazin-1-yl)-6-((2- C₂₂H₂₄N₆O₄S 468.529 15 4hydroxyethyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 82(Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-(4- C₂₁H₂₄N₆O₅S₂ 504.582 164 (phenylsulfonyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 83(Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₄H₂₆N₆O₄S 494.56617 4 2(1H)-yl)-6-((2- hydroxyethyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 84(Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-(5- C₂₃H₂₆N₆O₅S₂ 530.62 18 4(phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 85(Z)-5-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₄H₂₇N₇O₄S 509.58119 4 ((2-hydroxyethyl)(methyl)amino)pyrimidin-2-yl)-N-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 86(Z)-6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₃H₂₅N₇O₄S 495.55420 4 ((2-hydroxyethyl)(methyl)amino)pyrimidin-2-yl)-N-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxamide 87(Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₃H₂₄N₆O₄S480.539 21 4 6-((2-hydroxyethyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 88(Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-(6- C₂₂H₂₄N₆O₅S₂ 516.593 224 (phenylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 89(Z)-5-((6-(methyl(phenyl)amino)-2-(4- C₂₅H₂₄N₆O₂S 472.562 1 5phenylpiperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 90(Z)-5-((6-(methyl(phenyl)amino)-2-(4-(pyridin-3- C₂₄H₂₃N₇O₂S 473.55 2 5yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 91(Z)-5-((6-(methyl(phenyl)amino)-2-(4-(pyrimidin-5- C₂₃H₂₂N₈O₂S 474.538 35 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 92(Z)-5-((6-(methyl(phenyl)amino)-2-(4-(pyrimidin-2- C₂₃H₂₂N₈O₂S 474.538 45 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 93(Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₆H₂₅N₇O₃S 515.5875 5 (methyl(phenyl)amino)pyrimidin-2-yl)-N-phenylpiperazine-1-carboxamide 94(Z)-5-((2-(4-(1-ethylpiperidin-4-yl)piperazin-1-yl)-6- C₂₆H₃₃N₇O₂S507.651 6 5 (methyl(phenyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 95(Z)-5-((6-(methyl(phenyl)amino)-2-(4-(pyridin-4-yl)- C₂₅H₂₅N₇O₂S 487.5777 5 1,4-diazepan-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione96 (Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₂₇H₂₅N₇O₃S527.598 8 5 6-(methyl(phenyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 97(Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₇H₂₇N₇O₃S 529.6139 5 (methyl(phenyl)amino)pyrimidin-2-yl)-N-phenyl-1,4-diazepane-1-carboxamide 98(Z)-5-((6-(methyl(phenyl)amino)-2-(4-(6-methyl-2- C₂₉H₃₃N₉O₂S 571.696 105 (pyrrolidin-1-yl)pyrimidin-4-yl)-1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 99(Z)-5-((2-((2-(diethylamino)ethyl)(methyl)amino)-6- C₂₂H₂₈N₆O₂S 440.56211 5 (methyl(phenyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 100(Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₆H₂₃N₇O₄S₂561.635 12 5 6-(methyl(phenyl)amino)pyrimidin-2-yl)amino)ethyl)isoquinoline-5-sulfonamide 101(Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₄H₂₂N₆O₃S474.535 13 5 6-(methyl(phenyl)amino)pyrimidin-2-yl)amino)ethyl)benzamide 102(Z)-5-((6-(methyl(phenyl)amino)-2-((2-(4-oxo-3,4- C₂₅H₂₁N₇O₃S 499.544 145 dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 103(Z)-5-((2-(4-benzoylpiperazin-1-yl)-6- C₂₆H₂₄N₆O₃S 500.572 15 5(methyl(phenyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione104 (Z)-5-((6-(methyl(phenyl)amino)-2-(4- C₂₅H₂₄N₆O₄S₂ 536.626 16 5(phenylsulfonyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 105(Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₈H₂₆N₆O₃S 526.60917 5 2(1H)-yl)-6-(methyl(phenyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 106(Z)-5-((6-(methyl(phenyl)amino)-2-(5- C₂₇H₂₆N₆O₄S₂ 562.663 18 5(phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 107(Z)-5-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₈H₂₇N₇O₃S 541.62419 5 (methyl(phenyl)amino)pyrimidin-2-yl)-N-phenylhexahydropyrrolo[3,4-c]pyrrole-2 (1H)- carboxamide 108(Z)-6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₇H₂₅N₇O₃S 527.59820 5 (methyl(phenyl)amino)pyrimidin-2-yl)-N-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxamide 109(Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₇H₂₄N₆O₃S512.583 21 5 6-(methyl(phenyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 110(Z)-5-((6-(methyl(phenyl)amino)-2-(6- C₂₆H₂₄N₆O₄S₂ 548.637 22 5(phenylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 111(Z)-5-((6-(furan-2-ylmethoxy)-2-(4-phenylpiperazin-1- C₂₃H₂₁N₅O₄S463.509 1 6 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 112(Z)-5-((6-(furan-2-ylmethoxy)-2-(4-(pyridin-3- C₂₂H₂₀N₆O₄S 464.497 2 6yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 113(Z)-5-((6-(furan-2-ylmethoxy)-2-(4-(pyrimidin-5- C₂₁H₁₉N₇O₄S 465.485 3 6yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 114(Z)-5-((6-(furan-2-ylmethoxy)-2-(4-(pyrimidin-2- C₂₁H₁₉N₇O₄S 465.485 4 6yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 115(Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₄H₂₂N₆O₅S 506.5345 6 (furan-2-ylmethoxy)pyrimidin-2-yl)-N- phenylpiperazine-1-carboxamide116 (Z)-5-((2-(4-(1-ethylpiperidin-4-yl)piperazin-1-yl)-6- C₂₄H₃₀N₆O₄S498.598 6 6 (furan-2-ylmethoxy)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 117(Z)-5-((6-(furan-2-ylmethoxy)-2-(4-(pyridin-4-yl)-1,4- C₂₃H₂₂N₆O₄S478.524 7 6 diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 118 (Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)-C₂₅H₂₂N₆O₅S 518.544 8 6 6-(furan-2-ylmethoxy)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 119(Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₅H₂₄N₆O₅S 520.569 6 (furan-2-ylmethoxy)pyrimidin-2-yl)-N-phenyl-1,4-diazepane-1-carboxamide 120(Z)-5-((6-(furan-2-ylmethoxy)-2-(4-(6-methyl-2- C₂₇H₃₀N₈O₄S 562.643 10 6(pyrrolidin-1-yl)pyrimidin-4-yl)-1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 121(Z)-5-((2-((2-(diethylamino)ethyl)(methyl)amino)-6- C₂₀H₂₅N₅O₄S 431.50911 6 (furan-2-ylmethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione122 (Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₄H₂₀N₆O₆S₂552.582 12 6 6-(furan-2-ylmethoxy)pyrimidin-2-yl)amino)ethyl)isoquinoline-5-sulfonamide 123(Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₂H₁₉N₅O₅S465.482 13 6 6-(furan-2-ylmethoxy)pyrimidin-2- yl)amino)ethyl)benzamide124 (Z)-5-((6-(furan-2-ylmethoxy)-2-((2-(4-oxo-3,4- C₂₃H₁₈N₆O₅S 490.49114 6 dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 125(Z)-5-((2-(4-benzoylpiperazin-1-yl)-6-(furan-2- C₂₄H₂₁N₅O₅S 491.519 15 6ylmethoxy)pyrimidin-4-yl)methylene)thiazolidine-2,4- dione 126(Z)-5-((6-(furan-2-ylmethoxy)-2-(4- C₂₃H₂₁N₅O₆S₂ 527.573 16 6(phenylsulfonyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 127(Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₆H₂₃N₅O₅S 517.55617 6 2(1H)-yl)-6-(furan-2-ylmethoxy)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 128(Z)-5-((6-(furan-2-ylmethoxy)-2-(5- C₂₅H₂₃N₅O₆S₂ 553.61 18 6(phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 129(Z)-5-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₆H₂₄N₆O₅S 532.57119 6 (furan-2-ylmethoxy)pyrimidin-2-yl)-N-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 130(Z)-6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₅H₂₂N₆O₅S 518.54420 6 (furan-2-ylmethoxy)pyrimidin-2-yl)-N-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxamide 131(Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₅H₂₁N₅O₅S 503.5321 6 6-(furan-2-ylmethoxy)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 132(Z)-5-((6-(furan-2-ylmethoxy)-2-(6-(phenylsulfonyl)- C₂₄H₂₁N₅O₆S₂539.583 22 6 2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 133(Z)-5-((6-phenoxy-2-(4-phenylpiperazin-1- C₂₄H₂₁N₅O₃S 459.52 1 7yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 134(Z)-5-((6-phenoxy-2-(4-(pyridin-3-yl)piperazin-1- C₂₃H₂₀N₆O₃S 460.508 27 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 135(Z)-5-((6-phenoxy-2-(4-(pyrimidin-5-yl)piperazin-1- C₂₂H₁₉N₇O₃S 461.4963 7 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 136(Z)-5-((6-phenoxy-2-(4-(pyrimidin-2-yl)piperazin-1- C₂₂H₁₉N₇O₃S 461.4964 7 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 137(Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₅H₂₂N₆O₄S 502.5455 7 phenoxypyrimidin-2-yl)-N-phenylpiperazine-1- carboxamide 138(Z)-5-((2-(4-(1-ethylpiperidin-4-yl)piperazin-1-yl)-6- C₂₅H₃₀N₆O₃S494.609 6 7 phenoxypyrimidin-4-yl)methylene)thiazolidine-2,4- dione 139(Z)-5-((6-phenoxy-2-(4-(pyridin-4-yl)-1,4-diazepan-1- C₂₄H₂₂N₆O₃S474.535 7 7 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 140(Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₂₆H₂₂N₆O₄S514.556 8 7 6-phenoxypyrimidin-4-yl)methylene)thiazolidine-2,4- dione141 (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₆H₂₄N₆O₄S516.572 9 7 phenoxypyrimidin-2-yl)-N-phenyl-1,4-diazepane-1- carboxamide142 (Z)-5-((2-(4-(6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4- C₂₈H₃₀N₈O₃S558.655 10 7 yl)-1,4-diazepan-1-yl)-6-phenoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione 143(Z)-5-((2-((2-(diethylamino)ethyl)(methyl)amino)-6- C₂₁H₂₅N₅O₃S 427.5211 7 phenoxypyrimidin-4-yl)methylene)thiazolidine-2,4- dione 144(Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₅H₂₀N₆O₅S₂548.594 12 7 6-phenoxypyrimidin-2-yl)amino)ethyl)isoquinoline-5-sulfonamide 145 (Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)-C₂₃H₁₉N₅O₄S 461.493 13 7 6-phenoxypyrimidin-2-yl)amino)ethyl)benzamide146 (Z)-5-((2-((2-(4-oxo-3,4-dihydroquinazolin-2- C₂₄H₁₈N₆O₄S 486.503 147 yl)ethyl)amino)-6-phenoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione 147(Z)-5-((2-(4-benzoylpiperazin-1-yl)-6- C₂₅H₂₁N₅O₄S 487.53 15 7phenoxypyrimidin-4-yl)methylene)thiazolidine-2,4- dione 148(Z)-5-((6-phenoxy-2-(4-(phenylsulfonyl)piperazin-1- C₂₄H₂₁N₅O₅S₂ 523.58416 7 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 149(Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₇H₂₃N₅O₄S 513.56817 7 2(1H)-yl)-6-phenoxypyrimidin-4- yl)methylene)thiazolidine-2,4-dione150 (Z)-5-((6-phenoxy-2-(5- C₂₆H₂₃N₅O₅S₂ 549.621 18 7(phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 151(Z)-5-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₇H₂₄N₆O₄S 528.58219 7 phenoxypyrimidin-2-yl)-N-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 152(Z)-6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₆H₂₂N₆O₄S 514.55620 7 phenoxypyrimidin-2-yl)-N-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxamide 153(Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₆H₂₁N₅O₄S499.541 21 7 6-phenoxypyrimidin-4-yl)methylene)thiazolidine-2,4- dione154 (Z)-5-((6-phenoxy-2-(6-(phenylsulfonyl)-2,6- C₂₅H₂₁N₅O₅S₂ 535.595 227 diazaspiro[3.3]heptan-2-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 155(Z)-5-((6-(benzyloxy)-2-(4-phenylpiperazin-1- C₂₅H₂₃N₅O₃S 473.547 1 8yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 156(Z)-5-((6-(benzyloxy)-2-(4-(pyridin-3-yl)piperazin-1- C₂₄H₂₂N₆O₃S474.535 2 8 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 157(Z)-5-((6-(benzyloxy)-2-(4-(pyrimidin-5-yl)piperazin- C₂₃H₂₁N₇O₃S475.523 3 8 1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 158(Z)-5-((6-(benzyloxy)-2-(4-(pyrimidin-2-yl)piperazin- C₂₃H₂₁N₇O₃S475.523 4 8 1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 159(Z)-4-(4-(benzyloxy)-6-((2,4-dioxothiazolidin-5- C₂₆H₂₄N₆O₄S 516.572 5 8ylidene)methyl)pyrimidin-2-yl)-N-phenylpiperazine-1- carboxamide 160(Z)-5-((6-(benzyloxy)-2-(4-(1-ethylpiperidin-4- C₂₆H₃₂N₆O₃S 508.636 6 8yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 161(Z)-5-((6-(benzyloxy)-2-(4-(pyridin-4-yl)-1,4- C₂₅H₂₄N₆O₃S 488.561 7 8diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine- 2,4-dione 162(Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₂₇H₂₄N₆O₄S528.582 8 8 6-(benzyloxy)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 163 (Z)-4-(4-(benzyloxy)-6-((2,4-dioxothiazolidin-5-C₂₇H₂₆N₆O₄S 530.598 9 8 ylidene)methyl)pyrimidin-2-yl)-N-phenyl-1,4-diazepane-1-carboxamide 164(Z)-5-((6-(benzyloxy)-2-(4-(6-methyl-2-(pyrrolidin-1- C₂₉H₃₂N₈O₃S572.681 10 8 yl)pyrimidin-4-yl)-1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 165 (Z)-5-((6-(benzyloxy)-2-((2-C₂₂H₂₇N₅O₃S 441.546 11 8 (diethylamino)ethyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 166(Z)-N-(2-((4-(benzyloxy)-6-((2,4-dioxothiazolidin-5- C₂₆H₂₂N₆O₅S₂ 562.6212 8 ylidene)methyl)pyrimidin-2-yl)amino)ethyl)isoquinoline-5-sulfonamide 167(Z)-N-(2-((4-(benzyloxy)-6-((2,4-dioxothiazolidin-5- C₂₄H₂₁N₅O₄S 475.5213 8 ylidene)methyl)pyrimidin-2-yl)amino)ethyl)benzamide 168(Z)-5-((6-(benzyloxy)-2-((2-(4-oxo-3,4- C₂₅H₂₀N₆O₄S 500.529 14 8dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 169(Z)-5-((2-(4-benzoylpiperazin-1-yl)-6- C₂₆H₂₃N₅O₄S 501.557 15 8(benzyloxy)pyrimidin-4-yl)methylene)thiazolidine-2,4- dione 170(Z)-5-((6-(benzyloxy)-2-(4-(phenylsulfonyl)piperazin- C₂₅H₂₃N₅O₅S₂537.611 16 8 1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 171(Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₈H₂₅N₅O₄S 527.59417 8 2(1H)-yl)-6-(benzyloxy)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 172 (Z)-5-((6-(benzyloxy)-2-(5-C₂₇H₂₅N₅O₅S₂ 563.648 18 8(phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 173(Z)-5-(4-(benzyloxy)-6-((2,4-dioxothiazolidin-5- C₂₈H₂₆N₆O₄S 542.609 198 ylidene)methyl)pyrimidin-2-yl)-N-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 174(Z)-6-(4-(benzyloxy)-6-((2,4-dioxothiazolidin-5- C₂₇H₂₄N₆O₄S 528.582 208 ylidene)methyl)pyrimidin-2-yl)-N-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxamide 175(Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₇H₂₃N₅O₄S513.568 21 8 6-(benzyloxy)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 176 (Z)-5-((6-(benzyloxy)-2-(6-(phenylsulfonyl)-2,6-C₂₆H₂₃N₅O₅S₂ 549.621 22 8 diazaspiro[3.3]heptan-2-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 177(Z)-5-((6-(2-methoxyethoxy)-2-(4-phenylpiperazin-1- C₂₁H₂₃N₅O₄S 441.5031 9 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 178(Z)-5-((6-(2-methoxyethoxy)-2-(4-(pyridin-3- C₂₀H₂₂N₆O₄S 442.491 2 9yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 179(Z)-5-((6-(2-methoxyethoxy)-2-(4-(pyrimidin-5- C₁₉H₂₁N₇O₄S 443.48 3 9yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 180(Z)-5-((6-(2-methoxyethoxy)-2-(4-(pyrimidin-2- C₁₉H₂₁N₇O₄S 443.48 4 9yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 181(Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-(2- C₂₂H₂₄N₆O₅S484.528 5 9 methoxyethoxy)pyrimidin-2-yl)-N-phenylpiperazine-1-carboxamide 182 (Z)-5-((2-(4-(1-ethylpiperidin-4-yl)piperazin-1-yl)-6-C₂₂H₃₂N₆O₄S 476.592 6 9 (2-methoxyethoxy)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 183(Z)-5-((6-(2-methoxyethoxy)-2-(4-(pyridin-4-yl)-1,4- C₂₁H₂₄N₆O₄S 456.5187 9 diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine- 2,4-dione 184(Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₂₃H₂₄N₆O₅S496.539 8 9 6-(2-methoxyethoxy)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 185(Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-(2- C₂₃H₂₆N₆O₅S498.555 9 9 methoxyethoxy)pyrimidin-2-yl)-N-phenyl-1,4-diazepane-1-carboxamide 186(Z)-5-((6-(2-methoxyethoxy)-2-(4-(6-methyl-2- C₂₅H₃₂N₈O₄S 540.638 10 9(pyrrolidin-1-yl)pyrimidin-4-yl)-1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 187(Z)-5-((2-((2-(diethylamino)ethyl)(methyl)amino)-6- C₁₈H₂₇N₅O₄S 409.50311 9 (2-methoxyethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione188 (Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₂H₂₂N₆O₆S₂530.577 12 9 6-(2-methoxyethoxy)pyrimidin-2-yl)amino)ethyl)isoquinoline-5-sulfonamide 189(Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₀H₂₁N₅O₅S443.476 13 9 6-(2-methoxyethoxy)pyrimidin-2- yl)amino)ethyl)benzamide190 (Z)-5-((6-(2-methoxyethoxy)-2-((2-(4-oxo-3,4- C₂₁H₂₀N₆O₅S 468.486 149 dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 191(Z)-5-((2-(4-benzoylpiperazin-1-yl)-6-(2- C₂₂H₂₃N₅O₅S 469.514 15 9methoxyethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 192(Z)-5-((6-(2-methoxyethoxy)-2-(4- C₂₁H₂₃N₅O₆S₂ 505.567 16 9(phenylsulfonyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 193(Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₄H₂₅N₅O₅S 495.55117 9 2(1H)-yl)-6-(2-methoxyethoxy)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 194(Z)-5-((6-(2-methoxyethoxy)-2-(5- C₂₃H₂₅N₅O₆S₂ 531.605 18 9(phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 195(Z)-5-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-(2- C₂₄H₂₆N₆O₅S510.565 19 9 methoxyethoxy)pyrimidin-2-yl)-N-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 196(Z)-6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-(2- C₂₃H₂₄N₆O₅S496.539 20 9 methoxyethoxy)pyrimidin-2-yl)-N-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxamide 197(Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₃H₂₃N₅O₅S481.524 21 9 6-(2-methoxyethoxy)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 198(Z)-5-((6-(2-methoxyethoxy)-2-(6-(phenylsulfonyl)- C₂₂H₂₃N₅O₆S₂ 517.57822 9 2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 199(Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(4- C₂₂H₂₆N₆O₃S 454.545 1 10phenylpiperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione200 (Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(4-(pyridin-3- C₂₁H₂₅N₇O₃S455.533 2 10 yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 201(Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(4-(pyrimidin- C₂₀H₂₄N₈O₃S 456.5213 10 5-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 202(Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(4-(pyrimidin- C₂₀H₂₄N₈O₃S 456.5214 10 2-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 203(Z)-4-(4-(2-(dimethylamino)ethoxy)-6-((2,4- C₂₃H₂₇N₇O₄S 497.57 5 10dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-N-phenylpiperazine-1-carboxamide 204(Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(4-(1- C₂₃H₃₅N₇O₃S 489.634 6 10ethylpiperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 205(Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(4-(pyridin-4- C₂₂H₂₇N₇O₃S 469.567 10 yl)-1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 206(Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₂₄H₂₇N₇O₄S509.581 8 10 6-(2-(dimethylamino)ethoxy)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 207(Z)-4-(4-(2-(dimethylamino)ethoxy)-6-((2,4- C₂₄H₂₉N₇O₄S 511.597 9 10dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-N-phenyl-1,4-diazepane-1-carboxamide 208(Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(4-(6-methyl- C₂₆H₃₅N₉O₃S 553.6810 10 2-(pyrrolidin-1-yl)pyrimidin-4-yl)-1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 209(Z)-5-((2-((2-(diethylamino)ethyl)(methyl)amino)-6- C₁₉H₃₀N₆O₃S 422.54511 10 (2-(dimethylamino)ethoxy)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 210(Z)-N-(2-((4-(2-(dimethylamino)ethoxy)-6-((2,4- C₂₃H₂₅N₇O₅S₂ 543.619 1210 dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)amino)ethyl)isoquinoline-5-sulfonamide 211(Z)-N-(2-((4-(2-(dimethylamino)ethoxy)-6-((2,4- C₂₁H₂₄N₆O₄S 456.518 1310 dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)amino)ethyl)benzamide 212(Z)-5-((6-(2-(dimethylamino)ethoxy)-2-((2-(4-oxo-3,4- C₂₂H₂₃N₇O₄S481.528 14 10 dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 213(Z)-5-((2-(4-benzoylpiperazin-1-yl)-6-(2- C₂₃H₂₆N₆O₄S 482.555 15 10(dimethylamino)ethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione214 (Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(4- C₂₂H₂₆N₆O₅S₂ 518.609 16 10(phenylsulfonyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 215(Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₅H₂₈N₆O₄S 508.59317 10 2(1H)-yl)-6-(2-(dimethylamino)ethoxy)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 216(Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(5- C₂₄H₂₈N₆O₅S₂ 544.646 18 10(phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 217(Z)-5-(4-(2-(dimethylamino)ethoxy)-6-((2,4- C₂₅H₂₉N₇O₄S 523.607 19 10dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-N-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 218(Z)-6-(4-(2-(dimethylamino)ethoxy)-6-((2,4- C₂₄H₂₇N₇O₄S 509.581 20 10dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-N-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxamide 219(Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₄H₂₆N₆O₄S494.566 21 10 6-(2-(dimethylamino)ethoxy)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 220(Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(6- C₂₃H₂₆N₆O₅S₂ 530.62 22 10(phenylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 221(Z)-5-((4-(4-phenylpiperazin-1-yl)pyrimidin-2- C₁₈H₁₇N₅O₂S 367.425 1 11yl)methylene)thiazolidine-2,4-dione 222(Z)-5-((4-(4-(pyridin-3-yl)piperazin-1-yl)pyrimidin-2- C₁₇H₁₆N₆O₂S368.413 2 11 yl)methylene)thiazolidine-2,4-dione 223(Z)-5-((4-(4-(pyrimidin-5-yl)piperazin-1-yl)pyrimidin- C₁₆H₁₅N₇O₂S369.401 3 11 2-yl)methylene)thiazolidine-2,4-dione 224(Z)-5-((4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin- C₁₆H₁₅N₇O₂S369.401 4 11 2-yl)methylene)thiazolidine-2,4-dione 225(Z)-4-(2-((2,4-dioxothiazolidin-5- C₁₉H₁₈N₆O₃S 410.45 5 11ylidene)methyl)pyrimidin-4-yl)-N-phenylpiperazine-1- carboxamide 226(Z)-5-((4-(4-(1-ethylpiperidin-4-yl)piperazin-1- C₁₉H₂₆N₆O₂S 402.514 611 yl)pyrimidin-2-yl)methylene)thiazolidine-2,4-dione 227(Z)-5-((4-(4-(pyridin-4-yl)-1,4-diazepan-1- C₁₈H₁₈N₆O₂S 382.44 7 11yl)pyrimidin-2-yl)methylene)thiazolidine-2,4-dione 228(Z)-5-((4-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1- C₂₀H₁₈N₆O₃S 422.46 811 yl)pyrimidin-2-yl)methylene)thiazolidine-2,4-dione 229(Z)-4-(2-((2,4-dioxothiazolidin-5- C₂₀H₂₀N₆O₃S 424.476 9 11ylidene)methyl)pyrimidin-4-yl)-N-phenyl-1,4- diazepane-1-carboxamide 230(Z)-5-((4-(4-(6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4- C₂₂H₂₆N₈O₂S466.559 10 11 yl)-1,4-diazepan-1-yl)pyrimidin-2-yl)methylene)thiazolidine-2,4-dione 231 (Z)-5-((4-((2- C₁₅H₂₁N₅O₂S335.425 11 11 (diethylamino)ethyl)(methyl)amino)pyrimidin-2-yl)methylene)thiazolidine-2,4-dione 232(Z)-N-(2-((2-((2,4-dioxothiazolidin-5- C₁₉H₁₆N₆O₄S₂ 456.498 12 11ylidene)methyl)pyrimidin-4- yl)amino)ethyl)isoquinoline-5-sulfonamide233 (Z)-N-(2-((2-((2,4-dioxothiazolidin-5- C₁₇H₁₅N₅O₃S 369.398 13 11ylidene)methyl)pyrimidin-4-yl)amino)ethyl)benzamide 234(Z)-5-((4-((2-(4-oxo-3,4-dihydroquinazolin-2- C₁₈H₁₄N₆O₃S 394.407 14 11yl)ethyl)amino)pyrimidin-2-yl)methylene)thiazolidine- 2,4-dione 235(Z)-5-((4-(4-benzoylpiperazin-1-yl)pyrimidin-2- C₁₉H₁₇N₅O₃S 395.435 1511 yl)methylene)thiazolidine-2,4-dione 236(Z)-5-((4-(4-(phenylsulfonyl)piperazin-1-yl)pyrimidin- C₁₈H₁₇N₅O₄S₂431.489 16 11 2-yl)methylene)thiazolidine-2,4-dione 237(Z)-5-((4-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₁H₁₉N₅O₃S 421.47217 11 2(1H)-yl)pyrimidin-2-yl)methylene)thiazolidine-2,4- dione 238(Z)-5-((4-(5-(phenylsulfonyl)hexahydropyrrolo[3,4- C₂₀H₁₉N₅O₄S₂ 457.52618 11 c]pyrrol-2(1H)-yl)pyrimidin-2- yl)methylene)thiazolidine-2,4-dione239 (Z)-5-(2-((2,4-dioxothiazolidin-5- C₂₁H₂₀N₆O₃S 436.487 19 11ylidene)methyl)pyrimidin-4-yl)-N-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 240(Z)-6-(2-((2,4-dioxothiazolidin-5- C₂₀H₁₈N₆O₃S 422.46 20 11ylidene)methyl)pyrimidin-4-yl)-N-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxamide 241(Z)-5-((4-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2- C₂₀H₁₇N₅O₃S 407.446 2111 yl)pyrimidin-2-yl)methylene)thiazolidine-2,4-dione 242(Z)-5-((4-(6-(phenylsulfonyl)-2,6- C₁₉H₁₇N₅O₄S₂ 443.499 22 11diazaspiro[3.3]heptan-2-yl)pyrimidin-2-yl)methylene)thiazolidine-2,4-dione 243(Z)-5-((4-(4-phenylpiperazin-1-yl)-1,3,5-triazin-2- C₁₇H₁₆N₆O₂S 368.4131 12 yl)methylene)thiazolidine-2,4-dione 244(Z)-5-((4-(4-(pyridin-3-yl)piperazin-1-yl)-1,3,5-triazin- C₁₆H₁₅N₇O₂S369.401 2 12 2-yl)methylene)thiazolidine-2,4-dione 245(Z)-5-((4-(4-(pyrimidin-5-yl)piperazin-1-yl)-1,3,5- C₁₅H₁₄N₈O₂S 370.3893 12 triazin-2-yl)methylene)thiazolidine-2,4-dione 246(Z)-5-((4-(4-(pyrimidin-2-yl)piperazin-1-yl)-1,3,5- C₁₅H₁₄N₈O₂S 370.3894 12 triazin-2-yl)methylene)thiazolidine-2,4-dione 247(Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₁₈H₁₇N₇O₃S 411.438 512 1,3,5-triazin-2-yl)-N-phenylpiperazine-1-carboxamide 248(Z)-5-((4-(4-(1-ethylpiperidin-4-yl)piperazin-1-yl)- C₁₈H₂₅N₇O₂S 403.5026 12 1,3,5-triazin-2-yl)methylene)thiazolidine-2,4-dione 249(Z)-5-((4-(4-(pyridin-4-yl)-1,4-diazepan-1-yl)-1,3,5- C₁₇H₁₇N₇O₂S383.428 7 12 triazin-2-yl)methylene)thiazolidine-2,4-dione 250(Z)-5-((4-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₁₉H₁₇N₇O₃S423.448 8 12 1,3,5-triazin-2-yl)methylene)thiazolidine-2,4-dione 251(Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₁₉H₁₉N₇O₃S 425.464 912 1,3,5-triazin-2-yl)-N-phenyl-1,4-diazepane-1- carboxamide 252(Z)-5-((4-(4-(6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4- C₂₁H₂₅N₉O₂S467.547 10 12 yl)-1,4-diazepan-1-yl)-1,3,5-triazin-2-yl)methylene)thiazolidine-2,4-dione 253(Z)-5-((4-((2-(diethylamino)ethyl)(methyl)amino)- C₁₄H₂₀N₆O₂S 336.413 1112 1,3,5-triazin-2-yl)methylene)thiazolidine-2,4-dione 254(Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₁₈H₁₅N₇O₄S₂457.486 12 12 1,3,5-triazin-2-yl)amino)ethyl)isoquinoline-5- sulfonamide255 (Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₁₆H₁₄N₆O₃S370.386 13 12 1,3,5-triazin-2-yl)amino)ethyl)benzamide 256(Z)-5-((4-((2-(4-oxo-3,4-dihydroquinazolin-2- C₁₇H₁₃N₇O₃S 395.395 14 12yl)ethyl)amino)-1,3,5-triazin-2- yl)methylene)thiazolidine-2,4-dione 257(Z)-5-((4-(4-benzoylpiperazin-1-yl)-1,3,5-triazin-2- C₁₈H₁₆N₆O₃S 396.42315 12 yl)methylene)thiazolidine-2,4-dione 258(Z)-5-((4-(4-(phenylsulfonyl)piperazin-1-yl)-1,3,5- C₁₇H₁₆N₆O₄S₂ 432.47716 12 triazin-2-yl)methylene)thiazolidine-2,4-dione 259(Z)-5-((4-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₀H₁₈N₆O₃S 422.46 1712 2(1H)-yl)-1,3,5-triazin-2-yl)methylene)thiazolidine- 2,4-dione 260(Z)-5-((4-(5-(phenylsulfonyl)hexahydropyrrolo[3,4- C₁₉H₁₈N₆O₄S₂ 458.51418 12 c]pyrrol-2(1H)-yl)-1,3,5-triazin-2-yl)methylene)thiazolidine-2,4-dione 261(Z)-5-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₀H₁₉N₇O₃S 437.47519 12 1,3,5-triazin-2-yl)-N-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide 262(Z)-6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₁₉H₁₇N₇O₃S 423.44820 12 1,3,5-triazin-2-yl)-N-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxamide 263(Z)-5-((4-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₁₉H₁₆N₆O₃S408.434 21 12 1,3,5-triazin-2-yl)methylene)thiazolidine-2,4-dione 264(Z)-5-((4-(6-(phenylsulfonyl)-2,6- C₁₈H₁₆N₆O₄S₂ 444.487 22 12diazaspiro[3.3]heptan-2-yl)-1,3,5-triazin-2-yl)methylene)thiazolidine-2,4-dione

In addition, it may be convenient or desirable to prepare, purify,and/or handle the active compound in a chemically protected form. Theterm “chemically protected form,” as used herein, pertains to a compoundin which one or more reactive functional groups are protected fromundesirable chemical reactions (i.e., they have been modified with aprotecting group).

By protecting a reactive functional group, reactions involving otherunprotected reactive functional groups can be performed withoutaffecting the protected group; the protecting group may be removed,usually in a subsequent step, without substantially affecting theremainder of the molecule. See, for example, Protective Groups inOrganic Synthesis (T. Green and P. Wuts, Wiley, 1991), and ProtectiveGroups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; JohnWiley and Sons, 1999).

For example, a hydroxy group may be protected as an ether (—OR) or anester (—OC(═O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl(diphenylmethyl), or trityl (triphenylmethyl)ether; a trimethylsilyl ort-butyldimethylsilyl ether; or an acetyl ester (—OC(═O)CH₃, —OAc).

For example, an aldehyde or ketone group may be protected as an acetalor ketal, respectively, in which the carbonyl group (C(═O)) is convertedto a diether (C(OR)₂), by reaction with, for example, a primary alcohol.The aldehyde or ketone group is readily regenerated by hydrolysis usinga large excess of water in the presence of acid.

For example, an amine group may be protected, for example, as an amide(—NRC(═O)R) or a urethane (—NRC(═O)OR), for example, as: a methyl amide(—NHC(═O)CH₃); a benzyloxy amide (—NHC(═O)OCH₂C₆H₅NHCbz); as a t-butoxyamide (—NHC(═O)OC(CH₃)₃, —NHBoc); a 2-biphenyl-2-propoxy amide(—NHC(═O)OC(CH₃)₂C₆H₄C₆H₅NHBoc), as a 9-fluorenylmethoxy amide(—NHFmoc), as a 6-nitroveratryloxy amide (—NHNvoc), as a2-trimethylsilylethyloxy amide (—NHTeoc), as a 2,2,2-trichloroethyloxyamide (—NHTroc), as an allyloxy amide (—NHAlloc), as a2-(phenylsulfonyl)ethyloxy amide (—NHPsec); or, in suitable cases (e.g.,cyclic amines), as a nitroxide radical.

For example, a carboxylic acid group may be protected as an ester or anamide, for example, as: a benzyl ester; a t-butyl ester; a methyl ester;or a methyl amide.

For example, a thiol group may be protected as a thioether (—SR), forexample, as: a benzyl thioether; or an acetamidomethyl ether(—SCH₂NHC(═O)CH₃).

Pharmaceutical Compositions

One or more compounds of this invention can be administered to a mammalby themselves or in pharmaceutical compositions where they are mixedwith suitable carriers or excipient(s) at doses to treat or ameliorate adisease or condition as described herein. Mixtures of these compoundscan also be administered to the patient as a simple mixture or insuitable formulated pharmaceutical compositions. For example, one aspectof the invention relates to pharmaceutical composition comprising atherapeutically effective dose of a compound of formula I, or apharmaceutically acceptable salt, solvate, enantiomer or stereoisomerthereof; and a pharmaceutically acceptable diluent or carrier.

Techniques for formulation and administration of the compounds of theinstant application may be found in references well known to one ofordinary skill in the art, such as “Remington's PharmaceuticalSciences,” Mack Publishing Co., Easton, Pa., latest edition.

Suitable routes of administration may, for example, include oral,eyedrop, rectal, transmucosal, topical, or intestinal administration;parenteral delivery, including intramuscular, subcutaneous,intramedullary injections, as well as intrathecal, directintraventricular, intravenous, intraperitoneal, intranasal, orintraocular injections.

Alternatively, one may administer a compound in a local rather than asystemic manner, for example, via injection of the compound directlyinto an edematous site, often in a depot or sustained releaseformulation.

Furthermore, one may administer a compound in a targeted drug deliverysystem, for example, in a liposome coated with endothelial-cell-specificantibody.

The pharmaceutical compositions of the present invention may bemanufactured, e.g., by means of conventional mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping or lyophilizing processes.

Pharmaceutical compositions for use in accordance with the presentinvention thus may be formulated in a conventional manner using one ormore physiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

For injection, the agents of the invention may be formulated in aqueoussolutions, preferably in physiologically compatible buffers such asHanks' solution, Ringer's solution, or physiological saline buffer. Fortransmucosal administration, penetrants are used in the formulationappropriate to the barrier to be permeated. Such penetrants aregenerally known in the art.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained by combining the active compound with a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients include fillers suchas sugars, including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g., gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds can be formulated for parenteral administration byinjection, e.g., bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form forreconstitution before use with a suitable vehicle, e.g., sterilepyrogen-free water.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example, subcutaneously orintramuscularly or by intramuscular injection). Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives (for example, as asparingly soluble salt).

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are examples ofdelivery vehicles or carriers for hydrophobic drugs. Certain organicsolvents such as dimethysulfoxide also may be employed. Additionally,the compounds may be delivered using a sustained-release system, such assemi-permeable matrices of solid hydrophobic polymers containing thetherapeutic agent. Various sustained-release materials have beenestablished and are well known by those skilled in the art.Sustained-release capsules may, depending on their chemical nature,release the compounds for a few weeks up to over 100 days. Depending onthe chemical nature and the biological stability of the therapeuticreagent, additional strategies for protein stabilization may beemployed.

The pharmaceutical compositions may also comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymers,such as polyethylene glycols.

Methods of Treatment

Provided herein are methods of modulating the activity of CK1 andsubtypes thereof, CK2, the Wnt pathway, and/or the TGFβ pathway. Alsoprovided herein are methods of treating or preventing conditions anddiseases the course of which can be influenced by modulating theactivity of CK1 (e.g., CK1γ), CK2, the Wnt pathway, and/or the TGFβpathway. Such methods typically comprise administering to a subject inneed thereof a therapeutically effective amount of a compound orcomposition of the invention.

Also provided herein are methods of modulating the activity of PIM, suchas PIM 1, PIM 2 or PIM 3, the JAK/STAT pathway, and/or the mTOR pathway,and/or Pgp. Also provided herein are methods of treating or preventingconditions and diseases, the course of which can be influenced bymodulating the activity of the PIMs, the JAK/STAT pathway, and/or themTOR pathway, and/or Pgp. Such methods typically comprise administeringto a subject in need thereof a therapeutically effective amount of acompound or composition of the invention.

Various diseases, such as cancers, inflammation, and inflammatorydiseases (e.g., osteoarthritis and rheumatoid arthritis), andneurological conditions (e.g., Alzheimer's disease) andneurodegeneration can be treated by administration of modulators of CK1(e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway. Bone-relateddiseases and conditions, including osteoporosis and bone formation, alsocan be treated by administration of modulators of CK1 (e.g., CK1γ), CK2,the Wnt pathway and/or the TGFβ pathway. Bone restoration can befacilitated by administration of modulators of CK1 (e.g., CK1γ), CK2,the Wnt pathway and/or the TGFβ pathway. Additional conditions that canbe treated by administration of modulators of CK1 (e.g., CK1γ), CK2, theWnt pathway and/or the TGFβ pathway include hypoglycemia, metabolicsyndrome and diabetes. Modulators of CK1 (e.g., CK1γ), CK2, the Wntpathway and/or the TGFβ pathway are also useful for influencingapoptosis (e.g., increasing the rate of apoptosis in cancerous cells).Modulators of CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβpathway are also useful in treatment or prevention of aberrant embryonicdevelopment.

Based at least on the fact that increased CK1γ has been found to beassociated with certain cancers, a method for treating cancer in asubject comprises administering to the subject in need thereof atherapeutically effective amount of a compound that inhibits CK1γ. PIM1,PIM2, PIM3, the JAK/STAT pathway, and/or the mTOR pathway have also beenfound to be associated with certain cancers. Therefore, provided hereinis a method for treating cancer comprising administering to a subject inneed thereof a therapeutically effective amount of a compound thatinhibits PIM1 and/or PIM2 and/or PIM3.

PIM1, PIM2, and PIM3 have also been associated with protecting Pgp fromdegradation, which can regulate drug efflux and drug resistance.Therefore, provided herein is a method for treating malignanciescomprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound that inhibits PIM1 and/or PIM2 and/orPIM3 in conjunction with another drug, compound or material to abrogateresistance to the drug, compound or material.

The compounds described herein can be used for modulating cellproliferation, generally. Accordingly, diseases that may be treatedinclude hyperproliferative diseases, such as benign cell growth andmalignant cell growth.

Exemplary cancers that may be treated include leukemias, e.g., acutelymphoid leukemia and myeloid leukemia, and carcinomas, such ascolorectal carcinoma and hepatocarcinoma. Other cancers include AcuteLymphoblastic Leukemia; Acute Lymphoblastic Leukemia; Acute MyeloidLeukemia; Acute Myeloid Leukemia; Adrenocortical CarcinomaAdrenocortical Carcinoma; AIDS-Related Cancers; AIDS-Related Lymphoma;Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, ChildhoodCerebral; Basal Cell Carcinoma, see Skin Cancer (non-Melanoma); BileDuct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer; Bone Cancer,osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma; BrainTumor; Brain

Tumor, Brain Stem Glioma; Brain Tumor, Cerebellar Astrocytoma; BrainTumor, Cerebral Astrocytoma/Malignant Glioma; Brain Tumor, Ependymoma;Brain Tumor, Medulloblastoma; Brain Tumor, Supratentorial PrimitiveNeuroectodermal Tumors; Brain Tumor, Visual Pathway and HypothalamicGlioma; Brain Tumor; Breast Cancer; Breast Cancer and Pregnancy; BreastCancer; Breast Cancer, Male; Bronchial Adenomas/Carcinoids; Burkitt'sLymphoma; Carcinoid Tumor; Carcinoid Tumor, Gastrointestinal; Carcinomaof Unknown Primary; Central Nervous System Lymphoma, Primary; CerebellarAstrocytoma; Cerebral Astrocytoma/Malignant Glioma; Cervical Cancer;Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic MyelogenousLeukemia; Chronic Myeloproliferative Disorders; Colon Cancer; ColorectalCancer; Cutaneous T-Cell Lymphoma, see Mycosis Fungoides and SezarySyndrome; Endometrial Cancer; Ependymoma; Esophageal Cancer; EsophagealCancer; Ewing's Family of Tumors; Extracranial Germ Cell Tumor;Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer,Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer;Gastric (Stomach) Cancer; Gastric (Stomach) Cancer; GastrointestinalCarcinoid Tumor; Germ Cell Tumor, Extracranial; Germ Cell Tumor,Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor;Glioma; Glioma, Childhood Brain Stem; Glioma, Childhood CerebralAstrocytoma; Glioma, Childhood Visual Pathway and Hypothalamic; HairyCell Leukemia; Head and Neck Cancer; Hematologic (Blood) Cancer,Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver)Cancer, Childhood (Primary); Hodgkin's Lymphoma; Hodgkin's Lymphoma;Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamicand Visual Pathway Glioma; Intraocular Melanoma; Islet Cell Carcinoma(Endocrine Pancreas); Kaposi's Sarcoma; Kidney (Renal Cell) Cancer;Kidney Cancer; Laryngeal Cancer; Laryngeal Cancer; Leukemia, AcuteLymphoblastic; Leukemia, Acute Lymphoblastic; Leukemia, Acute Myeloid;Leukemia, Acute Myeloid; Leukemia, Chronic Lymphocytic; Leukemia;Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer;Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); LungCancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoma, AIDS-Related;Lymphoma, Burkitt's; Lymphoma, Cutaneous T-Cell, see Mycosis Fungoidesand Sezary Syndrome; Lymphoma, Hodgkin's; Lymphoma, Hodgkin's; Lymphoma,Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's; Lymphoma,Non-Hodgkin's; Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma,Primary Central Nervous System; Macroglobulinemia, Waldenstrom's;Malignant Fibrous Histiocytoma of Bone/Osteosarcoma; Medulloblastoma;Melanoma; Melanoma, Intraocular (Eye); Merkel Cell Carcinoma;Mesothelioma, Adult Malignant; Mesothelioma; Metastatic Squamous NeckCancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome;Multiple Myeloma/Plasma Cell Neoplasm' Mycosis Fungoides;Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases;Myelogenous Leukemia, Chronic; Myeloid Leukemia, Adult Acute; MyeloidLeukemia, Childhood Acute; Myeloma, Multiple; MyeloproliferativeDisorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer;Nasopharyngeal Cancer; Nasopharyngeal Cancer; Neuroblastoma;Non-Hodgkin's Lymphoma; Non-Hodgkin's Lymphoma; Non-Hodgkin's LymphomaDuring Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer; Oral CavityCancer, Lip and; Oropharyngeal Cancer; Osteosarcoma/Malignant FibrousHistiocytoma of Bone; Ovarian Cancer; Ovarian Epithelial Cancer; OvarianGerm Cell Tumor; Ovarian Low Malignant Potential Tumor; PancreaticCancer; Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; ParathyroidCancer; Penile Cancer; Pheochromocytoma; Pineoblastoma andSupratentorial Primitive Neuroectodermal Tumors; Pituitary Tumor; PlasmaCell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy andBreast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy andNon-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma;Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell(Kidney) Cancer; Renal Pelvis and Ureter, Transitional Cell Cancer;Retinoblastoma; Rhabdomyosarcoma; Salivary Gland Cancer; Salivary GlandCancer; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma,Soft Tissue; Sarcoma, Soft Tissue; Sarcoma, Uterine; Sezary Syndrome;Skin Cancer (non-Melanoma); Skin Cancer; Skin Cancer (Melanoma); SkinCarcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer;Soft Tissue Sarcoma; Soft Tissue Sarcoma; Squamous Cell Carcinoma, seeSkin Cancer (non-Melanoma); Squamous Neck Cancer with Occult Primary,Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer;Supratentorial Primitive Neuroectodermal Tumors; T-Cell Lymphoma,Cutaneous, see Mycosis Fungoides and Sezary Syndrome; Testicular Cancer;Thymoma; Thymoma and Thymic Carcinoma; Thyroid Cancer; Thyroid Cancer;Transitional Cell Cancer of the Renal Pelvis and Ureter; TrophoblasticTumor, Gestational; Unknown Primary Site, Carcinoma of; Unknown PrimarySite, Cancer of; Unusual Cancers of Childhood; Ureter and Renal Pelvis,Transitional Cell Cancer; Urethral Cancer; Uterine Cancer, Endometrial;Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma;Vulvar Cancer; Waldenstrom's Macroglobulinemia; Wilms' Tumor; andWomen's Cancers.

Neurologic diseases that may be treated include epilepsy, schizophrenia,bipolar disorder or other psychological and/or psychiatric disorders,neuropathies, skeletal muscle atrophy, and neurodegenerative diseases,e.g., a neurodegenerative disease. Exemplary neurodegenerative diseasesinclude. Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), andParkinson's disease. Another class of neurodegenerative diseasesincludes diseases caused at least in part by aggregation ofpoly-glutamine. Diseases of this class include: Huntington's Diseases,Spinalbulbar Muscular Atrophy (SBMA or Kennedy's Disease),Dentatorubropallidoluysian Atrophy (DRPLA), Spinocerebellar Ataxia 1(SCAT), Spinocerebellar Ataxia 2 (SCA2), Machado-Joseph Disease (MJD;SCA3), Spinocerebellar Ataxia 6 (SCA6), Spinocerebellar Ataxia 7 (SCAT),and Spinocerebellar Ataxia 12 (SCA12).

Any other disease in which the Wnt pathway, TGFβ pathway, JAK/STATpathway, the mTOR pathway, Pgp modulation, CK1, CK1γ, CK2, or PIMs playsa role may be treatable or preventable using compounds and methodsdescribed herein.

Dosage

As used herein, a “therapeutically effective amount” or “therapeuticallyeffective dose” is an amount of a compound of the invention or acombination of two or more such compounds, which inhibits, totally orpartially, the progression of the condition or alleviates, at leastpartially, one or more symptoms of the condition. A therapeuticallyeffective amount can also be an amount which is prophylacticallyeffective. The amount which is therapeutically effective will dependupon the patient's size and gender, the condition to be treated, theseverity of the condition and the result sought. For a given patient, atherapeutically effective amount may be determined by methods known tothose of skill in the art.

A therapeutically effective dose refers to that amount of the compoundthat results in amelioration of symptoms in a patient. Toxicity andtherapeutic efficacy of such compounds can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the maximum tolerated dose (MTD) and the ED₅₀(effective dose for 50% maximal response). The dose ratio between toxicand therapeutic effects is the therapeutic index and it can be expressedas the ratio between MTD and ED₅₀. The data obtained from these cellculture assays and animal studies can be used in formulating a range ofdosage for use in humans. The dosage of such compounds lies preferablywithin a range of circulating concentrations that include the ED₅₀ withlittle or no toxicity. The dosage may vary within this range dependingupon the dosage form employed and the route of administration utilized.The exact formulation, route of administration and dosage can be chosenby the individual physician in view of the patient's condition. In thetreatment of crises, the administration of an acute bolus or an infusionapproaching the MTD may be required to obtain a rapid response.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain theCK1, CK1γ, CK2, Piml-3, Wnt pathway, TGFβ pathway, JAK/STAT pathway,mTOR pathway, or Pgp modulating effects, or minimal effectiveconcentration (MEC). The MEC will vary for each compound but can beestimated from in vitro data. Dosages necessary to achieve the MEC willdepend on individual characteristics and route of administration. HPLCassays or bioassays can be used to determine plasma concentrations.

Dosage intervals can also be determined using the MEC value. Compoundsshould be administered using a regimen which maintains plasma levelsabove the MEC for 10-90% of the time, preferably between 30-90% and mostpreferably between 50-90% until the desired amelioration of symptoms isachieved. In cases of local administration or selective uptake, theeffective local concentration of the drug may not be related to plasmaconcentration.

The amount of composition administered will, of course, be dependent onthe subject being treated, on the subject's weight, the severity of theaffliction, the manner of administration and the judgment of theprescribing physician.

Kits

The compounds and compositions of the invention (e.g., compounds andcompositions of formula I) may, if desired, be presented in a pack ordispenser device which may contain one or more unit dosage formscontaining the active ingredient. The pack may for example comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration.Compositions comprising a compound of the invention formulated in acompatible pharmaceutical carrier may also be prepared, placed in anappropriate container, and labelled for treatment of an indicatedcondition. Instructions for use may also be provided.

EXEMPLIFICATION

The invention now being generally described, it will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.The geometric isomers depicted below are believed to be correct, butfinal structural assignment will be made via 2-D NMR experiments.Although the exemplary compounds described below are believed to be theZ-geometric isomers, the E-geometric isomers and mixtures of the E- andZ-isomers are also contemplated by the present disclosure.

Example 1

(E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1)

1,1-dimethoxy-N,N-dimethylmethanamine (100 g, 839 mmol, 1.02 equiv.) and1,1-dimethoxypropan-2-one (97 g, 821 mmol) were added and stirred at110° C. for 3 hours. The produced methanol was removed by a Dean-Starkapparatus. After the solution was cooled to room temperature, theremaining volatile materials were removed in vacuo to provide 130 g ofthe crude product, (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1)(130 g, 143 g theoretical, 91%). LC-MS m/z 283 (M+1). Reference: WO2006/0097341A1, pg 67.

Example 2

Sodium 4-(dimethoxymethyl)pyrimidine-2-thiolate (2)

A solution of thiourea (64.7 g, 850 mmol, 1.13 equiv.), sodiummethanolate (95%, 40.5 g, 751 mmol, 1.0 equiv.) in methanol (500 mL, 1.5M) was stirred at room temperature for 30 minutes. A solution of(E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1) (130 g, 751 mmol)in methanol (200 mL) was added and the reaction stirred at roomtemperature for 2 h. The crude sodium4-(dimethoxymethyl)pyrimidine-2-thiolate (2) was used directly in thenext step without further purification. LC-MS m/z 209 (M+1). Reference:WO 2006/0097341A1, pg 67.

Example 3

4-(dimethoxymethyl)-2-(methylthio)pyrimidine (3):

Iodomethane (128 g, 902 mmol, 1.20 equiv.) was added carefully to thecrude solution of sodium 4-(dimethoxymethyl)pyrimidine-2-thiolate (2)(156 g, 751 mmol) in methanol (700 mL, 1.1 M) while maintaining thereaction temperature below 28° C. using an ice-water bath for cooling.The resulting mixture was stirred at room temperature for 16 h. Afterremoval of the solvent under reduced pressure, the residue was dilutedwith water (300 mL) and extracted with ethyl acetate (2×150 mL). Thecombined organic layer was concentrated under reduced pressure and thecrude residue purified by passing through a short silica gel pad andwashing with diethyl ether (200 mL) to afford4-(dimethoxymethyl)-2-(methylthio)pyrimidine (3) as a brown oil (53.7 g,150 g theoretical, 35.7%). LC-MS m/z 201 (M+1). Reference: WO2006/0097341A1, pg 67.

Example 4

2-(methylthio)pyrimidine-4-carbaldehyde (4):

4-(dimethoxymethyl)-2-(methylthio)pyrimidine (3) (53.7 g, 268 mmol) wasadded carefully to 1.2 N aqueous HCl (300 mL, 268 mmol, 1.0 equiv.) andstirred at 60° C. for 3 hours. The reaction mixture was then cooled toroom temperature and neutralized by the slow addition of solid sodiumbicarbonate. The crude mixture was extracted with diethyl ether (3×150mL) and the combined organic layer was concentrated under reducedpressure to afford 2-(methylthio)pyrimidine-4-carbaldehyde (4) as ayellow solid (14.2 g, 41.5 g theoretical, 34%). LC-MS m/z 155 (M+1).Reference: WO 2006/009734 A1, pg 67.

Example 5

(Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione(5)

A 40 mL round-bottomed vial was charged with2-(methylthio)pyrimidine-4-carbaldehyde (4) (771 mg, 5 mmol),thiazolidine-2,4-dione (586 mg, 5 mmol, 1.0 equiv.), and piperidine (400μL, 4 mmol, 0.8 equiv.) in ethanol (20 mL, 0.25 M). The reaction mixturewas heated to 80° C. and shaken for 20 h. The resulting yellowprecipitate was isolated by filtration and washed with ethanol (1×20 mL)and dried in vacuo to afford(Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione(5) as a yellow solid (550 mg, 898 mg theoretical, 61%). LC-MS m/z 254(M+1).

Example 6

(Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione(6)

A mixture of(Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione(5) (3.5 g, 13.82 mmol) in THF (100 mL, 0.13 M) was treated with asolution of oxone (25.8 g, 41.5 mmol, 3.0 equiv.) in water (175 mL). Theresulting mixture was stirred at room temperature for 48 h. Theresulting precipitate was filtered and washed with water (20 mL) anddiethyl ether (20 mL) to afford(Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione(6) as a solid (2.48 g, 3.94 g theoretical, 63%). LC-MS m/z 286 (M+1).

Example 7

General Displacement Procedure 1:

2 dram round bottomed vials were charged with(Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione(6) (25 mg, 0.0877 mmol), DMSO (1 mL, 0.08 M), diisopropylethylamine (50μL, 0.288 mmol, 3.2 equiv.), and the appropriate amine (0.0877 mmol, 1.0equiv.). The reaction mixture was heated to 120° C. and shaken for 16 h.The solvent was removed under reduced pressure (Genevac HT-4) and thecrude residues were purified using reverse phase HPLC (MS-triggeredfraction collection) with an acetonitrile/water gradient andtrifluoroacetic acid as a modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4).

Example 8

(Z)-5-((2-(4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-(benzo[d][1,3]dioxol-5-ylmethyl)piperazine (16.6 mg, 37.4 mgtheoretical, 44.3%). LC-MS m/z 426.5 (M+1).

Example 9

(Z)-5-((2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-(p-tolyl)piperazine (12.5 mg, 33.6 mg theoretical, 37.2%). LC-MS m/z382.5 (M+1).

Example 10

(Z)-5-β2-(methyl(2-(pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andN-methyl-2-(pyridin-2-yl)ethanamine (13.7 mg, 30 mg theoretical, 45.6%).LC-MS m/z 342.4 (M+1).

Example 11

(Z)-5-((2-(4-isopropylpiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-isopropylpiperazine (15.3 mg, 29.3 mg theoretical, 52.1%). LC-MS m/z334.4 (M+1).

Example 12

(Z)-5-((2-(3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1,2,3,4-tetrahydroisoquinoline (0.1 mg, 29.8 mg theoretical, 0.3%).LC-MS m/z 339.4 (M+1).

Example 13

(Z)-5-((2-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-(pyridin-2-yl)piperazine (25.7 mg, 32.4 mg theoretical, 79.3%). LC-MSm/z 369.4 (M+1).

Example 14

(Z)-methyl1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)pyrrolidine-2-carboxylatewas prepared using the general displacement procedure andmethylpyrrolidine-2-carboxylate (3.1 mg, 29.4 mg theoretical, 10.5%).LC-MS m/z 335.4 (M+1).

Example 15

(Z)-5-β2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-methylpiperazine (0.1 mg, 26.9 mg theoretical, 0.4%). LC-MS m/z 306.4(M+1).

Example 16

(Z)-5-((2-(4-morpholinopiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and4-(piperidin-4-yl)morpholine (14.7 mg, 33 mg theoretical, 44.5%). LC-MSm/z 376.4 (M+1).

Example 17

(Z)-tert-butyl(1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)pyrrolidin-3-yl)carbamatewas prepared using the general displacement procedure and tert-butylpyrrolidin-3-ylcarbamate (0.1 mg, 34.4 mg theoretical, 0.3%). LC-MS m/z392.4 (M+1).

Example 18

(Z)-5-((2-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and2-(piperazin-1-yl)pyrimidine (3.1 mg, 32.5 mg theoretical, 9.5%). LC-MSm/z 370.4 (M+1).

Example 19

(Z)-5-((2-morpholinopyrimidin-4-yl)methylene)thiazolidine-2,4-dione wasprepared using the general displacement procedure and morpholine (7.8mg, 25.7 mg theoretical, 30.3%). LC-MS m/z 293.3 (M+1).

Example 20

(Z)-5-((2-(piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and piperidine(8.9 mg, 25.5 mg theoretical, 34.8%). LC-MS m/z 291.3 (M+1).

Example 21

(Z)-5-((2-(pyrrolidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and pyrrolidine(8.3 mg, 24.3 mg theoretical, 34.1%). LC-MS m/z 277.3 (M+1).

Example 22

(Z)-5-((2-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and4-(pyrrolidin-1-yl)piperidine (9.3 mg, 31.6 mg theoretical, 29.4%).LC-MS m/z 360.4 (M+1).

Example 23

(Z)-tert-butyl4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperazine-1-carboxylatewas prepared using the general displacement procedure and tert-butylpiperazine-1-carboxylate (6.7 mg, 34.4 mg theoretical, 19.5%). LC-MS m/z392.4 (M+1).

Example 24

(Z)-tert-butyl4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-1,4-diazepane-1-carboxylatewas prepared using the general displacement procedure and tert-butyl1,4-diazepane-1-carboxylate (5.1 mg, 35.7 mg theoretical, 14.3%). LC-MSm/z 406.5 (M+1).

Example 25

(Z)-5-((2-(4-(2-morpholino-2-oxoethyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-morpholino-2-(piperazin-1-yl)ethanone (11.4 mg, 36.8 mg theoretical,31%). LC-MS m/z 419.5 (M+1).

Example 26

(Z)-5-((2-(4-phenylpiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-phenylpiperazine (11.3 mg, 32.3 mg theoretical, 35%). LC-MS m/z 368.4(M+1).

Example 27

(Z)-5-((2-(methyl(phenethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andN-methyl-2-phenylethanamine (8.3 mg, 30 mg theoretical, 27.7%). LC-MSm/z 341.4 (M+1).

Example 28

(Z)-5-((2-(4-(pyridin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-(pyridin-4-yl)piperazine (7 mg, 32.4 mg theoretical, 21.6%). LC-MS m/z369.4 (M+1).

Example 29

(Z)-tert-butyl(1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)carbamatewas prepared using the general displacement procedure and tert-butylpiperidin-4-ylcarbamate (5.9 mg, 35.7 mg theoretical, 16.5%). LC-MS m/z406.5 (M+1).

Example 30

(Z)-tert-butyl((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-3-yl)methyl)carbamatewas prepared using the general displacement procedure and tert-butyl(piperidin-3-ylmethyl)carbamate (0.1 mg, 36.9 mg theoretical, 0.3%).LC-MS m/z 420.5 (M+1).

Example 31

(Z)-5-((2-(4-aminopiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butylpiperidin-4-ylcarbamate. The purified boc-protected was then treatedwith dichloromethane (1.0 mL), hydrochloric acid in methanol (500 μL,1.25 M)) and shaken at 50° C. for 16 h. The reaction mixture was thenconcentrated under reduced pressure (Genevac HT-4) to provide (1.7 mg,26.9 mg theoretical, 6.3%). LC-MS m/z 306.4 (M+1).

Example 32

General Displacement Procedure 2:

2 dram round-bottomed vials were charged with(Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione(25 mg, 0.0877 mmol), DMSO (1 mL, 0.08 M), diisopropylethylamine (50 μL,0.288 mmol, 3.2 equiv.), and the appropriate amine (0.0877 mmol, 1.0equiv.). The reaction mixture was heated to 110° C. and shaken for 24 h.The solvent was removed under reduced pressure (Genevac HT-4) and thecrude residues were purified using reverse phase HPLC (MS-triggeredfraction collection) with an acetonitrile/water gradient andtrifluoroacetic acid as a modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4).

Example 33

(Z)-5-((2-(4-benzoylpiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andphenyl(piperazin-1-yl)methanone (4.1 mg, 34.7 mg theoretical, 11.8%).LC-MS m/z 396 (M+1).

Example 34

(R,Z)-5-((2-(4-benzyl-3-(hydroxymethyl)-5-oxopiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and(R)-1-benzyl-6-(hydroxymethyl)piperazin-2-one (5.1 mg, 37.4 mgtheoretical, 13.6%). LC-MS m/z 426 (M+1).

Example 35

(Z)—N-(1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)pyrrolidin-3-yl)-N-ethylacetamidewas prepared using the general displacement procedure andN-ethyl-N-(pyrrolidin-3-yl)acetamide (12.1 mg, 31.8 mg theoretical,38%). LC-MS m/z 362 (M+1).

Example 36

(Z)-5-((2-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andN,N-dimethylpyrrolidin-3-amine (12.2 mg, 28.1 mg theoretical, 43.4%).LC-MS m/z 320 (M+1).

Example 37

(Z)-5-((2-(methyl(1-methylpyrrolidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andN,1-dimethylpyrrolidin-3-amine (1.1 mg, 28.1 mg theoretical, 3.9%).LC-MS m/z 320 (M+1).

Example 38

(Z)-5-((2-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and2-(piperazin-1-yl)ethanol (4.4 mg, 29.5 mg theoretical, 14.9%). LC-MSm/z 336 (M+1).

Example 39

(Z)-5-((2-(4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and2-(piperazin-1-yl)-4-(trifluoromethyl)pyrimidine (5.8 mg, 38.5 mgtheoretical, 15.1%). LC-MS m/z 438 (M+1).

Example 40

(Z)-5-((2-(4-(4-(benzyloxy)phenyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-(4-(benzyloxy)phenyl)piperazine (4 mg, 41.7 mg theoretical, 9.6%).LC-MS m/z 474 (M+1).

Example 41

(Z)-5-((2-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-(4-chloro-2-fluorophenyl)piperazine (4.8 mg, 36.9 mg theoretical,13%). LC-MS m/z 420 (M+1).

Example 42

(Z)-5-((2-(4-(4-(tert-butyl)phenyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-(4-(tert-butyl)phenyl)piperazine (3.7 mg, 37.2 mg theoretical, 10%).LC-MS m/z 424 (M+1).

Example 43

(Z)-5-((2-(4-(3,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-(3,5-bis(trifluoromethyl)phenyl)piperazine (3.8 mg, 44.3 mgtheoretical, 8.6%). LC-MS m/z 504 (M+1).

Example 44

(Z)-5-((2-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-(4-(trifluoromethyl)pyrimidin-2-yl)-1,4-diazepane (4.9 mg, 39.7 mgtheoretical, 12.3%). LC-MS m/z 452 (M+1).

Example 45

(Z)-5-((2-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-([1,1′-biphenyl]-4-yl)piperazine (1.2 mg, 39 mg theoretical, 3.1%).LC-MS m/z 444 (M+1).

Example 46

(Z)-5-((2-(4-(furan-2-carbonyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andfuran-2-yl(piperazin-1-yl)methanone (6 mg, 33.9 mg theoretical, 17.7%).LC-MS m/z 386 (M+1).

Example 47

(Z)-5-((2-(4-((4-fluorophenyl)(phenyl)methyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-((4-fluorophenyl)(phenyl)methyl)piperazine (14.4 mg, 41.8 mgtheoretical, 34.4%). LC-MS m/z 476 (M+1).

Example 48

(Z)-5-((2-(4-(naphthalen-1-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-(naphthalen-1-yl)piperazine (6.2 mg, 36.7 mg theoretical, 16.9%).LC-MS m/z 418 (M+1).

Example 49

(Z)-5-((2-(4-([1,1′-biphenyl]-3-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-([1,1′-biphenyl]-3-yl)piperazine (10.4 mg, 39 mg theoretical, 26.7%).LC-MS m/z 444 (M+1).

Example 50

(Z)-5-((2-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-((4-fluorophenyl)sulfonyl)piperazine (5.2 mg, 39.6 mg theoretical,13.1%). LC-MS m/z 450 (M+1).

Example 51

(Z)-1-tert-butyl 2-methyl4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperazine-1,2-dicarboxylatewas prepared using the general displacement procedure and 1-tert-butyl2-methyl piperazine-1,2-dicarboxylate (2.8 mg, 39.6 mg theoretical, 7%).LC-MS m/z 450 (M+1).

Example 52

(Z)-5-((2-(4-benzyl-3-(hydroxymethyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and(1-benzylpiperazin-2-yl)methanol (1.7 mg, 36.2 mg theoretical, 4.7%).LC-MS m/z 413 (M+1).

Example 53

(Z)-5-((2-(5-oxo-1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1,4-diazepan-5-one (1.1 mg, 28.1 mg theoretical, 3.9%). LC-MS m/z 320(M+1).

Example 54

(Z)-5-((2-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-(4-(trifluoromethyl)phenyl)piperazine (3.3 mg, 38.3 mg theoretical,8.6%). LC-MS m/z 436 (M+1).

Example 55

(Z)-5-((2-(4-cyclohexylpiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-cyclohexylpiperazine (10.7 mg, 32.9 mg theoretical, 32.5%). LC-MS m/z374 (M+1).

Example 56

(Z)-5-((2-(methyl(3-(piperidin-1-yl)propyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andN-methyl-3-(piperidin-1-yl)propan-1-amine (10.2 mg, 31.8 mg theoretical,32.1%). LC-MS m/z 362 (M+1).

Example 57

(Z)-5-((2-(4-((1-methylpiperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-((1-methylpiperidin-4-yl)methyl)piperazine (7.3 mg, 42.3 mgtheoretical, 17.2%). LC-MS m/z 403 (M+1).

Example 58

(Z)-1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)piperidine-4-carboxamidewas prepared using the general displacement procedure andN-(2-hydroxyethyl)piperidine-4-carboxamide (10.8 mg, 39.7 mgtheoretical, 27.2%). LC-MS m/z 378 (M+1).

Example 59

(Z)-5-((2-(4-(4-methylpiperazine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and(4-methylpiperazin-1-yl)(piperidin-4-yl)methanone (5.5 mg, 43.8 mgtheoretical, 12.6%). LC-MS m/z 417 (M+1).

Example 60

(Z)-5-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-methyl-4-(piperidin-4-yl)piperazine (12.4 mg, 40.9 mg theoretical,30.4%). LC-MS m/z 389 (M+1).

Example 61

(Z)-5-((2-(4-(dimethylamino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andN,N-dimethylpiperidin-4-amine (5 mg, 35.1 mg theoretical, 14.3%). LC-MSm/z 334 (M+1).

Example 62

(Z)-1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidine-4-carbonitrilewas prepared using the general displacement procedure andpiperidine-4-carbonitrile (7.5 mg, 33.2 mg theoretical, 22.6%). LC-MSm/z 316 (M+1).

Example 63

(Z)-5-((2-((2-hydroxy-2-phenylethyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and2-(methylamino)-1-phenylethanol (10.8 mg, 37.5 mg theoretical, 28.8%).LC-MS m/z 357 (M+1).

Example 64

General Displacement Procedure 3:

2 dram round-bottomed vials were charged with(Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione(50 mg, 0.175 mmol), DMSO (2 mL, 0.08 M), diisopropylethylamine (34 μL,0.193 mmol, 1.1 equiv.), and the appropriate amine (0.175 mmol, 1.0equiv.). The reaction mixture was heated to 100° C. and shaken for 24 h.The solvent was removed under reduced pressure (Genevac HT-4). The crudewas then charged with 2 mL DCE and 500 μL of TFA and shaken for 24 h.The solvent was removed under reduced pressure (Genevac HT-4) and thecrude residues were purified using reverse phase HPLC (MS-triggeredfraction collection) with an acetonitrile/water gradient andtrifluoroacetic acid as a modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4).

Example 65

(Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butyl(piperidin-4-ylmethyl)carbamate (49 mg, 55.9 mg theoretical, 88%). LC-MSm/z 320 (M+1).

Example 66

(Z)-5-((2-(methyl(piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butyl3-(methylamino)piperidine-1-carboxylate (2.3 mg, 55.9 mg theoretical,4.1%). LC-MS m/z 320 (M+1).

Example 67

(Z)-5-((2-(3-methylpiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butyl2-methylpiperazine-1-carboxylate (1.5 mg, 53.4 mg theoretical, 2.8%).LC-MS m/z 306 (M+1).

Example 68

(Z)-5-((2-(piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butylpiperazine-1-carboxylate (17.7 mg, 51 mg theoretical, 34.7%). LC-MS m/z292 (M+1).

Example 69

(Z)-5-((2-(1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butyl1,4-diazepane-1-carboxylate (15.2 mg, 53.4 mg theoretical, 28.4%). LC-MSm/z 306 (M+1).

Example 70

(Z)-5-((2-(3-aminopyrrolidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butylpyrrolidin-3-ylcarbamate (16.5 mg, 51 mg theoretical, 32.4%). LC-MS m/z292 (M+1).

Example 71

(Z)-5-((2-(3-aminopiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butylpiperidin-3-ylcarbamate (16.9 mg, 29.8 mg theoretical, 53.4%). LC-MS m/z306 (M+1).

Example 72 Synthesis of(Z)-5-((6-(2-methoxyethoxy)-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione

A 25 mL round-bottomed flask was charged with 2-methoxyethanol (57 μL, 1equiv.) and THF (2.5 mL). 60% NaH in oil (21 mg, 1.1 equiv.) was addedat 0° C. under argon. The reaction mixture was stirred for 5 min at −5°C. and for 1 h 15 min at RT. Methyl 2,6-dichloropyrimidine-4-carboxylate(150 mg, 1 equiv.) dissolved in THF (1 mL) was added over 5 min at −78°C. The reaction mixture was stirred for 4 h warming from −78° C. to 0°C. LC-MS after 3 h (−15° C.) showed 2 peaks (2:1 ratio) with the desiredmass at 1.57 min and 1.67 min (M+1=247 & 249). The reaction mixture wasquenched with 10% NH₄Cl (5 mL) at 0° C. The aqueous layer was extractedwith EtOAc (3×10 mL). The combined organic layer was dried over Na₂SO₄and concentrated under reduced pressure to provide 161 mg of a crudemixture of methyl 2-chloro-6-(2-methoxyethoxy)pyrimidine-4-carboxylateand methyl 6-chloro-2-(2-methoxyethoxy)pyrimidine-4-carboxylate whichwas partially separated by flash chromatography on silica gel (10 g,Hexanes/EtOAc 9:1 to 7:3).

F1: 47 mg pure desired isomer 6-alkoxy (26%, 179 mg theoretical)F2: 19.3 mg mixture of isomers (11%)F3: 28.8 mg pure undesired isomer 2-alkoxy (16%)

A 25 mL round bottomed flask was charged with methyl2-chloro-6-(2-methoxyethoxy)pyrimidine-4-carboxylate [SAD105-047F1] (45mg, 1 equiv.) and CH₂Cl₂ (1 mL). 1 M DIBAL-H (0.2 mL, 1.1 equiv.) wasadded at −78° C. over 2 min under argon. The reaction mixture wasstirred for 3 h at −78° C. but the LC-MS still showed a lot of startingmaterial. Additional 1 M DIBAL-H (0.27 mL, 1.4 equiv.) was added at −78°C. over 2 min under argon and after 0.5 h LC-MS showed no more startingmaterial but mostly 1 peak at 1.20 min (M+1=217, M+l+MeOH=249). Thereaction mixture was quenched with MeOH (0.5 mL) and then with 10% NH₄Cl(1 mL). The reaction mixture was warmed to RT and then the solvent wasconcentrated under reduced pressure. The residue was diluted with 10%NH₄Cl (4 mL). The aqueous layer was extracted with EtOAc (3×10 mL). Thecombined organic layer was dried over Na₂SO₄ and concentrated underreduced pressure to provide 41.9 mg of the crude2-chloro-6-(2-methoxyethoxy)pyrimidine-4-carbaldehyde as a yellow oilwhich was used in the next step without further purification, (H NMR δ:9.91 (s, 1H); 7.23 (s, 1H); 4.59-4.64 (m, 2H), 3.7-3.8 (m, 2H); 3.44 (s,3H).

Crude 2-chloro-6-(2-methoxyethoxy)pyrimidine-4-carbaldehyde (sad105-052,41.9 mg) was dissolved in ethanol (1.5 mL) and was added to a 10 mL vialcontaining the thiazolidine-dione (21.3 mg, 0.18 mmol) and the1-(p-tolyl)piperazine (39.3 mg, 0.18 mmol). The reaction mixture wasshaken at 80° C. for 15.5 h. LC-MS showed a peak with the desired massat 2.18 min (M+1=456). The solvent was concentrated under reducedpressure and the residue was dissolved in EtOAc (20 mL) and washed withsaturated NaHCO₃ (10 mL). The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure to provide 85.7 mg of brown oil.Purification by flash chromatography (SiO₂,10 g, Hexanes/EtOAc 9:1 to6:4 to 1:1) provided 11.5 mg (13.9% 2 steps, 83 mg theoretical) of pure(Z)-5-((6-(2-methoxyethoxy)-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dioneas a yellow solid.

Example 73 Synthesis of(Z)-5-((6-methoxy-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione

A 40 mL round-bottomed vial was charged with methanol (120 μL of 200 μLMeOH in 1 mL Acetonitrile, 1 equiv.), K₂CO₃ (67 mg, 1 equiv.), methyl2,6-dichloropyrimidine-4-carboxylate (100 mg, 1 equiv.), andacetonitrile (2 mL). The reaction mixture was shaken for 2.5 h at RT butLC-MS showed only starting material. The reaction mixture was thenshaken for 1 h at 85° C. LC-MS showed the formation of a small amount ofdesired product (1.51 min, M+1=203). Methanol (0.200 mL, 10 equiv.) wasadded and the reaction mixture was shaken for 15 h at 85° C. LC-MSshowed mostly 1 peak in the UV and MS at 1.53 min and a tiny amount ofbis-methoxypyrimidine. The solid precipitate was filtered off and thefiltrate was evaporated to give 89 mg (91% crude yield, theoretical 98mg) of crude desired product. ¹H NMR showed an 11:1 mixture of desiredproduct and bis-methoxypyrimidine side product (M+1=199). The materialwas used in the next step without further purification.

A 25 mL round-bottomed flask was charged with methyl2-chloro-6-methoxypyrimidine-4-carboxylate [sad105-055 crude] (74 mg, 1equiv.) under argon. 1M DIBAL-H in dichloromethane (0.73 mL, 2 equiv.)was added over 5 min and the reaction mixture was stirred at −78° C. for45 min. After 0.5 h, LC-MS showed the reaction was complete. Thereaction was quenched at −78° C. with methanol (0.5 mL) and then with10% NH₄Cl (2 mL). The solvents were concentrated under reduced pressureand the residue was diluted with 10% NH₄Cl (3 mL). The aqueous layer wasextracted with EtOAc (3×10 mL). The combined organic layer was driedover Na₂SO₄ and concentrated under reduced pressure to provide the crudeproduct 2-chloro-6-methoxypyrimidine-4-carbaldehyde as an orange oil (76mg, 63 mg theoretical, 121%). LC-MS m/z: 205.0: (M+1+MeOH, hemiacetalwith methanol). Some over-reduced alcohol was also observed in the crude(2.17 min, M+1=175). The crude aldehyde was used directly in the nextstep without further purification.

Crude 2-chloro-6-methoxypyrimidine-4-carbaldehyde (sad105-058, 76 mg)was dissolved in ethanol (2 mL) and was added to a 10 mL vial containingthe thiazolidine-dione (42.8 mg, 0.37 mmol., 1 equiv.) and the1-(p-tolyl)piperazine (70.8 mg, 0.40 mmol, 1.1 equiv.). The mixture wasshaken for 45 h at 80° C. and for 15 h at 90° C. producing aprecipitate. LC-MS of the solution showed some product at (M+1=412) andsome intermediate at (M+1=430). The desired product crashed out of thesolution and the LC-MS of the solution does not reflect well theconversion of the reaction. The yellow solid was filtered using aPasteur pipette through a pad of glass wool and the solid was rinsedwith EtOH (4×0.5 mL). The ethanol filtrate contains some desiredproduct. The solid was re-dissolved in CH₂Cl₂ and the insoluble solidwas filtered off. The filtrate was concentrated under reduced pressureto provide 20 mg of the desired product(Z)-5-((6-methoxy-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione(97.3% pure). The insoluble solid was partitioned between saturatedNaHCO₃ (3 mL) and CH₂Cl₂ (2×5 mL). The organic layer was dried overNa₂SO₄ and concentrated under reduced pressure to provide an additional13.4 mg of the desired product (total 33.4 mg, 150 mg theoretical, 22%).LC-MS m/z: 412 (M+1).

Example 74 Synthesis of(Z)-5-((2-(4-(p-tolyl)piperazin-1-yl)pyridin-4-yl)methylene)thiazolidine-2,4-dione

A 40 mL round-bottomed vial was charged with methyl2-chloroisonicotinate (200 mg, 1.17 mmol, 1 equiv.) and1-(p-tolyl)piperazine (205 mg, 1.17 mmol, 1 equiv.). Toluene (3 mL) andDMSO (3 mL) were added followed by potassium carbonate (403 mg, 2.9mmol, 2.5 equiv.). The mixture was shaken for 18 h at 100° C. LC-MSafter 18 h showed a peak at 1.68 min with the desired mass (M+1=312)with the chloropyridine starting material co-eluting (M+1=172). Thereaction mixture was diluted with water (5 mL) and the aqueous layer wasextracted with CH₂Cl₂ (3×10 mL). The combined organic layer was driedover Na₂SO₄ and then concentrated under reduced pressure. The crudemixture was purified on silica gel (10 g, Hexanes/EtOAc 9:1 to 1:1) toprovide the desired product as white crystals (27 mg, 67 mg theoretical,40%).

A 25 mL round-bottomed flask was charged with methyl2-(4-(p-tolyl)piperazin-1-yl)isonicotinate (27 mg, 0.087 mmol, 1 equiv.)and CH₂Cl₂ (1 mL). 1 M DIBAL-H in CH₂Cl₂ (130 μL, 0.13 mmol, 1.5 equiv.)was added under argon at −78° C. over 2 min. The reaction mixture wasquenched with MeOH (0.5 mL) at −78° C. The LC-MS of the crude mixtureshowed a 1:1 mixture of the alcohol (1.21 min, M+1=284) and the aldehydeas a hemiacetal with methanol (1.38 min, M+1+MeOH=314.3). The crudealdehyde was used directly in the next step without any furtherpurification.

Crude 2-(4-(p-tolyl)piperazin-1-yl)isonicotinaldehyde [sad105-080] wasdissolved in ethanol (1 mL) and was added to a 10 mL vial containing thethiazolidine-dione (10.2 mg, 0.087 mmol) and the 1-(p-tolyl)piperazine(5.9 mg, 0.087 mmol). The reaction mixture was shaken at 90° C. for 19.5h. LC-MS showed a new peak with the desired mass at 1.78 min (M+1=381).The reaction was concentrated under reduced pressure and the residue waspurified by flash chromatography (SiO₂,10 g, Hexanes/EtOAc 9:1 to 4:6)to provide 10.1 mg (30% over two steps, 33.1 mg theoretical) of(Z)-5-(2-(4-(p-tolyl)piperazin-1-yl)pyridin-4-yl)methylene)thiazolidine-2,4-dioneas a yellow solid. The yellow solid was dissolved in hot EtOH (0.5 mL).On cooling a yellow solid precipitated, which was filtered through a padof glass wool and washed with 0.25 mL ethanol. The solid wasre-dissolved in CH₂Cl₂ and was concentrated under reduced pressure toprovide 1.7 mg of the title product. LC-MS m/z: (M+1=381).

Example 75 Synthesis of(Z)-5-((6-(4-(p-tolyl)piperazin-1-yl)pyridin-2-yl)methylene)thiazolidine-2,4-dione

A 40 mL round-bottomed vial was charged with thiazolidine-2,4-dione (300mg, 2.56 mmol, 1 equiv.) and 6-bromopicolinaldehyde (477 mg, 2.56 mmol,1 equiv.). Toluene (5 mL, 0.5 M), glacial acetic acid (22 μL, 0.38 mmol,0.15 equiv.), and piperidine (25 μL, 0.25 mmol, 0.1 equiv.) were addedand the vial was purged with argon. The mixture was shaken for 16 h at125° C. The resulting solid was collected by filtration and then washedwith acetone (3×5 mL). The solid was dried under reduced pressure toprovide (Z)-5-((6-bromopyridin-2-yl)methylene)thiazolidine-2,4-dione(439 mg, 731 mg theoretical, 60%). LC-MS m/z: 286 (M+1).

An 8 mL round bottomed vial was charged with 1-(p-tolyl)piperazine (56mg, 0.318 mmol, 1 equiv.) and DMSO (1 mL, 0.3 M), DiPEA (105 μL, 0.636mmol, 2 equiv.),(Z)-5-((6-bromopyridin-2-yl)methylene)thiazolidine-2,4-dione (91 mg,0.318 mmol, 1 equiv.), and the vial was purged with argon. The mixturewas shaken for 48 h at 110° C. The reaction mixture was then partitionedbetween CH₂Cl₂ (10 mL) and sat. NaCl (20 mL). The aqueous layer was backextracted with CH₂Cl₂ (2×15 mL) and the combined organic layer was driedover xxx and concentrated under reduced pressure to provide an orangeresidue. The orange residue was triturated with ether (3×15 mL) toprovide(Z)-5-((6-(4-(p-tolyl)piperazin-1-yl)pyridin-2-yl)methylene)thiazolidine-2,4-dioneas an orange solid (65 mg, 122 mg theoretical, 53%). LC-MS m/z: 382(M+1).

Example 76

(Z)-5-((6-(methyl(phenethyl)amino)pyridin-2-yl)methylene)thiazolidine-2,4-dione

An 8 mL round-bottomed vial was charged with N-methyl-2-phenylethanamine(43 mg, 0.318 mmol, 1 equiv.) and DMSO (1 mL, 0.3 M), DiPEA (105 μL,0.636 mmol, 2 equiv.),(Z)-5-((6-bromopyridin-2-yl)methylene)thiazolidine-2,4-dione (91 mg,0.318 mmol, 1 equiv.), and the vial was purged with argon. The mixturewas shaken for 48 h at 110° C. The reaction mixture was then partitionedbetween CH₂Cl₂ (10 mL) and sat. NaCl (20 mL). The aqueous layer was backextracted with CH₂Cl₂ (2×15 mL) and the combined organic layer was driedover xxx and concentrated under reduced pressure to provide an orangeresidue. The orange residue was triturated with ether (3×15 mL) toprovide(Z)-5-((6-(methyl(phenethyl)amino)pyridin-2-yl)methylene)thiazolidine-2,4-dioneas an orange film (2.6 mg, 175 mg theoretical, 5%). LC-MS m/z: 340(M+1).

Example 77 General Procedure 1 for the Preparation of Amino-Analogs

Methyl 2,6-dichloropyrimidine-4-carboxylate (200 mg, 0.966 mmol) in 2 mLof THF was treated with DIPEA (185 μL, 1.06 mmol) and the reaction wasthen cooled to 0° C. A solution of the appropriate amine (1 equiv.,0.966 mmol) in 2 mL of THF was then added slowly to the reactionmixture. The reaction mixture was shaken for 2 h and then concentratedunder reduced pressure to provide a light yellow crude product, whichwas used without any further purification.

The light yellow crude product (1 equiv.) was treated with DCM (2 mL).The reaction mixture was then cooled to −70° C. and treated dropwisewith 1 M DIBALH (180 μL, 1.1 equiv.) and stirred for 2 h. Another 100 μLof DIBALH was added dropwise and stirred for an additional 3 h. MeOH (1mL) was then added to quench the reaction. The reaction mixture was thenallowed to warm to room temperature and partitioned between water (5 mL)and DCM (5 mL). The DCM layer was collected and concentrated underreduced pressure. Flash chromatography using 50%-80% EtOAc/Hexanesprovided the desired aldehyde.

The aldehyde was treated with thiazolidine-2,4-dione (1 equiv.) and1-(p-tolyl)piperazine (1.1 equiv.) in 2 mL of EtOH. The reaction mixturewas then heated to 85° C. for 16 h and then further heated to 95° C. for24 h. The reaction mixture was then concentrated and purified by Biotagechromatography using 1:1 hexanes/EtOAc to provide the finalamino-analogs.

Example 78

(Z)-5-((6-(methyl(phenethyl)amino)-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using General Procedure 1 for the Preparation ofAmino-Analogs and N-methyl-2-phenylethanamine (4.2 mg, 90 mgtheoretical, 5%, 3 steps). LC-MS m/z: 515 (M+1).

Example 79

(Z)-5-((6-(benzyl(methyl)amino)-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using General Procedure 1 for the Preparation ofAmino-Analogs and N-methylbenzylamine (5.1 mg, 85 mg theoretical, 6%, 3steps). LC-MS m/z: 501 (M+1).

Example 80

(Z)-5-((6-((2-methoxyethyl)(methyl)amino)-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andN-methyl-1-phenylmethanamine (34 mg, 142 mg theoretical, 23.9%, 3steps). LC-MS m/z 501: (M+1).

Example 81 General Procedure 2 for the Preparation of Amino-Analogs

Methyl 2,6-dichloropyrimidine-4-carboxylate (200 mg, 0.966 mmol) in 2 mLof THF was treated with DIPEA (185 μL, 1.06 mmol) and then cooled to 0°C. A solution of the appropriate amine (1 equiv., 0.966 mmol) in 2 mL ofTHF was then added slowly. The reaction mixture was shaken for 2 h andconcentrated under reduced pressure to provide a light yellow crudeproduct, which was used without any further purification.

The crude material was treated with 2 mL of EtOH, DIPEA (1.1 equiv.),and 1-(p-tolyl)piperazine (1 equiv.). The reaction mixture was thenheated to 90° C. for 2 d. LCMS showed the desired product along with theEtO version of the ester. The reaction mixture was then concentratedunder reduced pressure and purified using a Biotage with 10-100%EtOAc/Hexanes to provide the desired di-aminoester intermediate.

The di-aminoester intermediate was treated with DCM (2 mL) and cooled to−10° C. DIBALH (3 equiv.) was added dropwise and the reaction mixturewas allowed to warm to room temperature and stirred for 1 h. Methanol (1mL) was added to quench the reaction and then allowed to stir for 30min. The reaction mixture was then partitioned between DCM (10 mL) andH₂O (10 mL). The aqueous layer was back extracted with DCM (2×10 mL) andthe combined organic layer was concentrated under reduced pressure. Thecrude residue was purified on silica gel using 5-10% MeOH/DCM to providethe desired alcohol.

The alcohol (1 equiv.) was treated with 2 mL of DCM and the reactionmixture was cooled to 0° C. and treated with 1.4 mL of 15% Dess Martinreagent in DCM. The reaction mixture was stirred for 1 h and treatedwith an additional portion of Dess Martin reagent (1.1 equiv.) at 0° C.,and the reaction mixture was allowed to warm to room temperature andstirred for 1 h. The reaction mixture was then concentrated underreduced pressure and the crude residue was purified by flashchromatography using 5-10% MeOH/DCM to provide the desired aldehyde.

The aldehyde was treated with thiazolidine-2,4-dione (1 equiv.),piperidine (0.8 equiv.), and 2 mL of EtOH. The reaction mixture was thenheated to 85° C. for 16 h and then concentrated under reduced pressure.The residue was then triturated with DCM (2 mL), MeOH (2 mL), and EtOAc(2 mL) to provide the final amino-analogs.

Example 82

(Z)-5-((6-(methyl(2-(pyridin-2-yl)ethyl)amino)-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andN-methyl-2-(pyridin-2-yl)ethanamine (12.7 mg, 160 mg theoretical, 1.7%,5 steps). LC-MS m/z: 516 (M+1).

Example 83

(Z)-5-((6-((2-methoxyethyl)(methyl)amino)-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and2-methoxy-N-methylethanamine (34 mg, 680 mg theoretical, 5%, 5 steps).LC-MS m/z: 469 (M+1).

Example 84

(Z)-2-(2,4-dioxo-5-((2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidin-3-yl)acetamide

To 10 mg of(Z)-5-((2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas added 4 mg of 2-bromoacetamide, 4 mg of potassium carbonate, and 0.5mL of DMF. The reaction mixture was heated to 55° C. for 4 h,concentrated under reduced pressure, and purified using reverse phaseHPLC (MS-triggered fraction collection) with an acetonitrile/watergradient using trifluoroacetic acid as a modifier. The pure fractionswere then concentrated under reduced pressure (Genevac HT-4) to provide(Z)-2-(2,4-dioxo-5-((2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidin-3-yl)acetamide(4 mg, 11.5 mg theoretical, 35%). LC-MS m/z: 439 (M+1).

Example 85

General Displacement Procedure:

2 dram round-bottomed vials were charged with(Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione(25 mg, 0.0877 mmol) prepared according to the general procedure, DMSO(1 mL, 0.08 M), diisopropylethylamine (50 μL, 0.288 mmol, 3.2 equiv.),and the appropriate amine (0.0877 mmol, 1.0 equiv.). The reactionmixture was heated to 110° C. and shaken for 24 h. The solvent wasremoved under reduced pressure (Genevac HT-4) and the crude residueswere purified using reverse phase HPLC (MS-triggered fractioncollection) with an acetonitrile/water gradient and trifluoroacetic acidas a modifier. The pure fractions were then concentrated under reducedpressure (Genevac HT-4).

Example 86

(Z)-5-((2-(4-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and5-(piperidin-4-yl)-3-(pyridin-4-yl)-1,2,4-oxadiazole (6 mg, 45.8 mgtheoretical, 13%). LC-MS m/z 436.4 (M+1).

Example 87

(Z)-5-((2-(butylmethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andN-methylbutan-1-amine (12.5 mg, 30.7 mg theoretical, 40.7%). LC-MS m/z293.3 (M+1).

Example 88

(Z)-5-((2-(isoquinolin-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure1,2,3,4-tetrahydroisoquinoline (2 mg, 35 mg theoretical, 5.7%). LC-MSm/z 337.1 (M+1).

Example 89

(Z)-5-((2-(methyl(pyridin-4-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andN-methylpyridin-4-amine (11.7 mg, 32.9 mg theoretical, 35.5%). LC-MS m/z314.3 (M+1).

Example 90

(Z)-5-((2-(7-amino-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1,2,3,4-tetrahydroisoquinolin-7-amine (12.8 mg, 37.2 mg theoretical,34.4%). LC-MS m/z 354.3 (M+1).

Example 91

(Z)-5-((2-(3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (4.2 mg, 39.7 mg theoretical,10.6%). LC-MS m/z 378.4 (M+1).

Example 92

(Z)-5-((2-(((1-methylpiperidin-4-yl)methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-(methylpiperidin-4-yl)methanamine (7.4 mg, 29.2 mg theoretical,25.3%). LC-MS m/z 334.1 (M+1).

Example 93

(Z)-5-((2-(4-(2-(dimethylamino)ethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andN,N-dimethyl-2-(piperidin-4-yl)ethanamine (20.6 mg, 38.0 mg theoretical,54.2%). LC-MS m/z 362.2 (M+1).

Example 94

(Z)-5-((2-(4-(1H-indol-3-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and3-(piperidin-4-yl)-1H-indole (7.2 mg, 42.6 mg theoretical, 16.8%). LC-MSm/z 406.1 (M+1).

Example 95

(Z)-5-((2-(4-(1H-indol-3-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andN,N-dimethyl-1-(piperidin-4-yl)methanamine (23.1 mg, 36.5 mgtheoretical, 63.2%). LC-MS m/z 348.1 (M+1).

Example 96

(Z)-5-((2-(3-fluoropiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and3-fluoropiperidine (7.7 mg, 32.4 mg theoretical, 23.7%). LC-MS m/z 309.1(M+1).

Example 97

(Z)-5-((2-(4-methylpiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and4-methylpiperidine (16.4 mg, 32 mg theoretical, 51.2%). LC-MS m/z 305.1(M+1).

Example 98

(Z)-5-((2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andpiperidin-4-ylmethanol (17.8 mg, 33.7 mg theoretical, 52.8%). LC-MS m/z321.1 (M+1).

Example 99

(Z)-5-((2-(3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and3,5-dimethylpiperidine (1.3 mg, 33.5 mg theoretical, 3.9%). LC-MS m/z319.1 (M+1).

Example 100

(Z)-5-((2-(8-methyl-2,8-diazaspiro[5.5]undecan-2-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and2-methyl-2,8-diazaspiro[5.5]undecane (23.5 mg, 39.3 mg theoretical,59.8%). LC-MS m/z 374.2 (M+1).

Example 101

(Z)-5-((2-(3-(piperidin-1-ylmethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-(piperidin-3-ylmethyl)piperidine (21.8 mg, 40.7 mg theoretical,53.5%). LC-MS m/z 388.5 (M+1).

Example 102

(Z)-5-((2-(2-(2-hydroxyethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and2-(piperidin-2-yl)ethanol (10.1 mg, 35.2 mg theoretical, 28.7%). LC-MSm/z 335.1 (M+1).

Example 103

(Z)-5-((2-(3-(1H-pyrazol-1-yl)azetidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-(azetidin-3-yl)-1H-pyrazole (24.3 mg, 34.5 mg theoretical, 70.4%).LC-MS m/z 329.1 (M+1).

Example 104

(Z)-5-((2-(3-((dimethylamino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andN,N-dimethyl-1-(piperidin-3-yl)methanamine (23.4 mg, 36.5 mgtheoretical, 64.1%). LC-MS m/z 348.4 (M+1).

Example 105

(Z)-5-((2-(8-benzyl-2,8-diazaspiro[5.5]undecan-2-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and2-benzyl-2,8-diazaspiro[5.5]undecane (15.3 mg, 47.3 mg theoretical,32.4%). LC-MS m/z 450.5 (M+1).

Example 106

(Z)-5-((2-(4-(2-hydroxyethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and2-(piperidin-4-yl)ethanol (18.1 mg, 47.2 mg theoretical, 38.4%). LC-MSm/z 335.1 (M+1).

Example 107

(Z)-5-((2-(4-(2-(piperidin-1-yl)ethyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-(2-(piperidin-1-yl)ethyl)piperazine (36.6 mg, 66.3 mg theoretical,55.2%). LC-MS m/z 403.2 (M+1).

Example 108

(Z)-5-((2-(2-methylpiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and2-methylpiperidine (2.5 mg, 32 mg theoretical, 7.8%). LC-MS m/z 305.1(M+1).

Example 109

(Z)-5-((2-(4-hydroxypiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and piperidin-4-ol(19.9 mg, 33.7 mg theoretical, 52.8%). LC-MS m/z 321.1 (M+1).

Example 110

(Z)-5-((2-(4-fluoropiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and4-fluoropiperidine (12 mg, 32.4 mg theoretical, 37%). LC-MS m/z 309.1(M+1).

Example 111

(Z)-5-((2-(3-(pyrrolidin-1-ylmethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and3-(pyrrolidin-1-ylmethyl)piperidine (4.3 mg, 39.3 mg theoretical, 11%).LC-MS m/z 374.5 (M+1).

Example 112

(Z)-5-((2-((2-(dimethylamino)ethyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andN1,N1,N2-trimethylethane-1,2-diamine (5.6 mg, 32.3 mg theoretical,17.3%). LC-MS m/z 308.4 (M+1).

Example 113

(S,Z)-5-((2-((1-hydroxybutan-2-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and amine (6.6 mg,30.9 mg theoretical, 21.3%). LC-MS m/z 295.1 (M+1).

Example 114

(Z)-5-((2-(3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and(S)-2-aminobutan-1-ol (13.5 mg, 33.7 mg theoretical, 40.1%). LC-MS m/z321.1 (M+1).

Example 115

(Z)-5-((2-(4,4-bis(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andpiperidine-4,4-diyldimethanol (10 mg, 36.8 mg theoretical, 27.1%). LC-MSm/z 351.1 (M+1).

Example 116

(Z)-5-((2-(3-hydroxypiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and piperidin-3-ol(6.3 mg, 32.2 mg theoretical, 19.6%). LC-MS m/z 307.1 (M+1).

Example 117

(Z)-5-((2-(3-methylpiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and3-methylpiperidine (10.3 mg, 32 mg theoretical, 32.2%). LC-MS m/z 305.1(M+1).

Example 118

(S,Z)-5-((2-(methyl(1-methylpiperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and(S)—N,1-dimethylpiperidin-3-amine (11.2 mg, 58.4 mg theoretical, 19.2%).LC-MS m/z 334.1 (M+1).

Example 119

(Z)-5-((2-(cyclohexyl(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andN-methylcyclohexanamine (3.4 mg, 33.5 mg theoretical, 10.2%). LC-MS m/z319.1 (M+1).

Example 120

(Z)-5-((2-(5-amino-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1,2,3,4-tetrahydroisoquinolin-5-amine (8.2 mg, 37.2 mg theoretical,22%). LC-MS m/z 354.1 (M+1).

Example 121

(Z)-5-((2-(cyclohexylamino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andcyclohexanamine (3.6 mg, 32 mg theoretical, 11.2%). LC-MS m/z 305.1(M+1).

Example 122

(Z)-1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidine-4-carboxamidewas prepared using the general displacement procedure andpiperidine-4-carboxamide (16.7 mg, 35.1 mg theoretical, 47.6%). LC-MSm/z 334.1 (M+1).

Example 123

(Z)-5-((2-((4-(m-tolylamino)-5,6,7,8-tetrahydroquinazolin-6-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andN4-(m-tolyl)-5,6,7,8-tetrahydroquinazoline-4,6-diamine (5.2 mg, 48.3 mgtheoretical, 10.8%). LC-MS m/z 460.5 (M+1).

Example 124

(Z)-5-((2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (12.4 mg, 38.2 mgtheoretical, 32.4%). LC-MS m/z 437.1 (M+1).

Example 125

(Z)-5-((2-(3-(3-ethyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and3-ethyl-5-(piperidin-3-yl)-1,2,4-oxadiazole (11.9 mg, 33.9 mgtheoretical, 35.1%). LC-MS m/z 387.1 (M+1).

Example 126

(Z)-5-((2-(4-(4,6-diamino-1,3,5-triazin-2-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and6-(piperidin-4-yl)-1,3,5-triazine-2,4-diamine (13.0 mg, 35.0 mgtheoretical, 37.1%). LC-MS m/z 400.1 (M+1).

Example 127

(Z)-5-((2-(3-((1H-benzo[d]imidazol-2-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and2-(piperidin-3-ylmethyl)-1H-benzo[d]imidazole (29.3 mg, 44.2 mgtheoretical, 66.3%). LC-MS m/z 421.5 (M+1).

Example 128

(Z)-5-((2-(3-(4-methyl-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and4-methyl-2-(piperidin-3-yl)-1H-benzo[d]imidazole (18.9 mg, 44.2 mgtheoretical, 42.7%). LC-MS m/z 421.5 (M+1).

Example 129

(Z)-5-((2-(4-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and3-(piperidin-4-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine(16.2 mg, 44.7 mg theoretical, 36.2%). LC-MS m/z 426.5 (M+1).

Example 130

(Z)-5-((2-(((1-ethyl-1H-pyrazol-5-yl)methyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-(1-ethyl-1H-pyrazol-5-yl)-N-methylmethanamine (7.2 mg, 36.2 mgtheoretical, 20%). LC-MS m/z 345.1 (M+1).

Example 131

(Z)-5-((2-(3-(6-hydroxy-2-methylpyrimidin-4-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and2-methyl-6-(piperidin-3-yl)pyrimidin-4-ol (16.8 mg, 41.9 mg theoretical,40.1%). LC-MS m/z 399.1 (M+1).

Example 132

(Z)-5-((2-(3-([1,2,4]triazolo[4,3-a]pyridin-3-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and3-(piperidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (11 mg, 42.8 mgtheoretical, 25.7%). LC-MS m/z 408.5 (M+1).

Example 133

(Z)-5-((2-(4-amino-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1,2,3,4-tetrahydroisoquinolin-4-amine (1.4 mg, 37.2 mg theoretical,3.8%). LC-MS m/z 354.1 (M+1).

Example 134

(Z)-5-((2-(4-(1H-tetrazol-5-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and4-(1H-tetrazol-5-yl)piperidine (4 mg, 37.7 mg theoretical, 10.6%). LC-MSm/z 359.1 (M+1).

Example 135

(Z)-5-((2-(methyl(thiophen-3-ylmethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andN-methyl-1-(thiophen-3-yl)methanamine (7.5 mg, 35 mg theoretical,21.5%). LC-MS m/z 333.0 (M+1).

Example 136

(Z)-5-((2-(2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1,3,8-triazaspiro[4.5]decane-2,4-dione (15.2 mg, 39.4 mg theoretical,38.6%). LC-MS m/z 375.1 (M+1).

Example 137

(Z)-5-((2-(((1H-benzo[d]imidazol-2-yl)methyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1-(1H-benzo[d]imidazol-2-yl)-N-methylmethanamine (6.6 mg, 38.5 mgtheoretical, 17%). LC-MS m/z 367.1 (M+1).

Example 138

(Z)-5-((2-((3-aminobenzyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and3-((methylamino)methyl)aniline (19.7 mg, 35.9 mg theoretical, 54.9%).LC-MS m/z 342.1 (M+1).

Example 139

(Z)-5-((2-((2-(1H-indol-3-yl)ethyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and2-(1H-indol-3-yl)-N-methylethanamine (8.3 mg, 39.9 mg theoretical,20.8%). LC-MS m/z 380.4 (M+1).

Example 140

(Z)-5-((2-((1,2,3,4-tetrahydroquinolin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and1,2,3,4-tetrahydroquinolin-3-amine (5 mg, 37.2 mg theoretical, 13.5%).LC-MS m/z 354.1 (M+1).

Example 141 Displacement/De-Protection of Mono-Boc Diamines

Example 142

(R,Z)-5-((2-(methyl(piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and (R)-tert-butyl3-(methylamino)piperidine-1-carboxylate. The crude protected amine wasthen treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. Thesolvent was removed under reduced pressure (Genevac HT-4) and the cruderesidues were purified using reverse phase HPLC (MS-triggered fractioncollection) with an acetonitrile/water or methanol/water gradient andtrifluoroacetic acid as a modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) (3.1 mg, 55.9 mgtheoretical, 5.5%). LC-MS m/z 320.1 (M+1).

Example 143

(S,Z)-5-((2-(methyl(piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and (S)-tert-butyl3-(methylamino)piperidine-1-carboxylate. The crude protected amine wasthen treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. Thesolvent was removed under reduced pressure (Genevac HT-4) and the cruderesidues were purified using reverse phase HPLC (MS-triggered fractioncollection) with an acetonitrile/water or methanol/water gradient andtrifluoroacetic acid as a modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) (3.2 mg, 55.9 mgtheoretical, 5.7%). LC-MS m/z 320.1 (M+1).

Example 144

(S,Z)-5-((2-(piperidin-3-ylamino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and (R)-tert-butyl3-aminopiperidine-1-carboxylate. The crude protected amine was thentreated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solventwas removed under reduced pressure (Genevac HT-4) and the crude residueswere purified using reverse phase HPLC (MS-triggered fractioncollection) with an acetonitrile/water or methanol/water gradient andtrifluoroacetic acid as a modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) (6.9 mg, 32.1 mgtheoretical, 21.5%). LC-MS m/z 306.1 (M+1).

Example 145

(R,Z)-5-((2-(piperidin-3-ylamino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and (S)-tert-butyl3-aminopiperidine-1-carboxylate. The crude protected amine was thentreated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solventwas removed under reduced pressure (Genevac HT-4) and the crude residueswere purified using reverse phase HPLC (MS-triggered fractioncollection) with an acetonitrile/water or methanol/water gradient andtrifluoroacetic acid as a modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) (3.8 mg, 32.1 mgtheoretical, 11.8%). LC-MS m/z 306.1 (M+1).

Example 146

(Z)-5-((2-((piperidin-2-ylmethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butyl2-(aminomethyl)piperidine-1-carboxylate. The crude protected amine wasthen treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. Thesolvent was removed under reduced pressure (Genevac HT-4) and the cruderesidues were purified using reverse phase HPLC (MS-triggered fractioncollection) with an acetonitrile/water or methanol/water gradient andtrifluoroacetic acid as a modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) (10.7 mg, 45.6 mgtheoretical, 23.5%). LC-MS m/z 320.1 (M+1).

Example 147

(Z)-5-((2-((piperidin-4-ylmethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butyl4-(aminomethyl)piperidine-1-carboxylate. The crude protected amine wasthen treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. Thesolvent was removed under reduced pressure (Genevac HT-4) and the cruderesidues were purified using reverse phase HPLC (MS-triggered fractioncollection) with an acetonitrile/water or methanol/water gradient andtrifluoroacetic acid as a modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) (5.3 mg, 33.5 mgtheoretical, 15.8%). LC-MS m/z 320.1 (M+1).

Example 148

(R,Z)-5-((2-((piperidin-3-ylmethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and (S)-tert-butyl3-(aminomethyl)piperidine-1-carboxylate. The crude protected amine wasthen treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. Thesolvent was removed under reduced pressure (Genevac HT-4) and the cruderesidues were purified using reverse phase HPLC (MS-triggered fractioncollection) with an acetonitrile/water or methanol/water gradient andtrifluoroacetic acid as a modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) (7.3 mg, 33.5 mgtheoretical, 21.8%). LC-MS m/z 320.1 (M+1).

Example 149

(Z)-5-((2-(methyl(piperidin-3-ylmethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butyl3-((methylamino)methyl)piperidine-1-carboxylate. The crude protectedamine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24h. The solvent was removed under reduced pressure (Genevac HT-4) and thecrude residues were purified using reverse phase HPLC (MS-triggeredfraction collection) with an acetonitrile/water or methanol/watergradient and trifluoroacetic acid as a modifier. The pure fractions werethen concentrated under reduced pressure (Genevac HT-4) (21.6 mg, 35 mgtheoretical, 61.7%). LC-MS m/z 334.1 (M+1).

Example 150

(Z)-5-((2-(3-((methylamino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butylmethyl(piperidin-3-ylmethyl)carbamate. The crude protected amine wasthen treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. Thesolvent was removed under reduced pressure (Genevac HT-4) and the cruderesidues were purified using reverse phase HPLC (MS-triggered fractioncollection) with an acetonitrile/water or methanol/water gradient andtrifluoroacetic acid as a modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) (17.9 mg, 35 mgtheoretical, 51.1%). LC-MS m/z 334.1 (M+1).

Example 151

(Z)-5-((2-(methyl(piperidin-4-ylmethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butyl4-((methylamino)methyl)piperidine-1-carboxylate. The crude protectedamine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24h. The solvent was removed under reduced pressure (Genevac HT-4) and thecrude residues were purified using reverse phase HPLC (MS-triggeredfraction collection) with an acetonitrile/water or methanol/watergradient and trifluoroacetic acid as a modifier. The pure fractions werethen concentrated under reduced pressure (Genevac HT-4) (6.5 mg, 35 mgtheoretical, 18.6%). LC-MS m/z 334.1 (M+1).

Example 152

(S,Z)-5-((2-((piperidin-3-ylmethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and (R)-tert-butyl3-((methylamino)methyl)piperidine-1-carboxylate. The crude protectedamine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24h. The solvent was removed under reduced pressure (Genevac HT-4) and thecrude residues were purified using reverse phase HPLC (MS-triggeredfraction collection) with an acetonitrile/water or methanol/watergradient and trifluoroacetic acid as a modifier. The pure fractions werethen concentrated under reduced pressure (Genevac HT-4) (11.2 mg, 33.5mg theoretical, 33.4%). LC-MS m/z 320.1 (M+1).

Example 153

(Z)-5-((2-((2-aminoethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butyl(2-aminoethyl)carbamate. The crude protected amine was then treated with2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removedunder reduced pressure (Genevac HT-4) and the crude residues werepurified using reverse phase HPLC (MS-triggered fraction collection)with an acetonitrile/water or methanol/water gradient andtrifluoroacetic acid as a modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) (10.7 mg, 27.9 mgtheoretical, 38.4%). LC-MS m/z 266.1 (M+1).

Example 154

(Z)-5-((2-(3-(methylamino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butylmethyl(piperidin-3-yl)carbamate. The crude protected amine was thentreated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solventwas removed under reduced pressure (Genevac HT-4) and the crude residueswere purified using reverse phase HPLC (MS-triggered fractioncollection) with an acetonitrile/water or methanol/water gradient andtrifluoroacetic acid as a modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) (26.9 mg, 33.5 mgtheoretical, 80%). LC-MS m/z 320.1 (M+1).

Example 155

(Z)-5-((2-(octahydro-1,5-naphthyridin-1(2H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butyloctahydro-1,5-naphthyridine-1(2H)-carboxylate. The crude protected aminewas then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h.The solvent was removed under reduced pressure (Genevac HT-4) and thecrude residues were purified using reverse phase HPLC (MS-triggeredfraction collection) with an acetonitrile/water or methanol/watergradient and trifluoroacetic acid as a modifier. The pure fractions werethen concentrated under reduced pressure (Genevac HT-4) (7.2 mg, 36.3 mgtheoretical, 19.8%). LC-MS m/z 346.1 (M+1).

Example 156

(Z)-5-((2-((3-aminobenzyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butyl(3-(aminomethyl)phenyl)carbamate. The crude protected amine was thentreated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solventwas removed under reduced pressure (Genevac HT-4) and the crude residueswere purified using reverse phase HPLC (MS-triggered fractioncollection) with an acetonitrile/water or methanol/water gradient andtrifluoroacetic acid as a modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) (6.5 mg, 28.7 mgtheoretical, 22.7%). LC-MS m/z 328.1 (M+1).

Example 157

(Z)-5-((2-((5-phenylpiperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butyl3-amino-5-phenylpiperidine-1-carboxylate. The crude protected amine wasthen treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. Thesolvent was removed under reduced pressure (Genevac HT-4) and the cruderesidues were purified using reverse phase HPLC (MS-triggered fractioncollection) with an acetonitrile/water or methanol/water gradient andtrifluoroacetic acid as a modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) (5.6 mg, 33.4 mgtheoretical, 16.8%). LC-MS m/z 382.1 (M+1).

Example 158

(Z)-5-((2-((4-phenylpiperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butyl3-amino-4-phenylpiperidine-1-carboxylate. The crude protected amine wasthen treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. Thesolvent was removed under reduced pressure (Genevac HT-4) and the cruderesidues were purified using reverse phase HPLC (MS-triggered fractioncollection) with an acetonitrile/water or methanol/water gradient andtrifluoroacetic acid as a modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) (5.7 mg, 33.4 mgtheoretical, 17.1%). LC-MS m/z 382.1 (M+1).

Example 159

(Z)-5-((2-((3-(aminomethyl)benzyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butyl3-(aminomethyl)benzylcarbamate. The crude protected amine was thentreated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solventwas removed under reduced pressure (Genevac HT-4) and the crude residueswere purified using reverse phase HPLC (MS-triggered fractioncollection) with an acetonitrile/water or methanol/water gradient andtrifluoroacetic acid as a modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) (16.6 mg, 35.8 mgtheoretical, 46.3%). LC-MS m/z 342.1 (M+1).

Example 160

(Z)-5-((2-(octahydro-1,5-naphthyridin-1(2H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and3-((tert-butoxycarbonyl)amino)-3-(piperidin-4-yl)propanoic acid. Thecrude protected amine was then treated with 2 mL DCE and 500 μL of TFAand shaken for 24 h. The solvent was removed under reduced pressure(Genevac HT-4) and the crude residues were purified using reverse phaseHPLC (MS-triggered fraction collection) with an acetonitrile/water ormethanol/water gradient and trifluoroacetic acid as a modifier. The purefractions were then concentrated under reduced pressure (Genevac HT-4)(24.6 mg, 11.8 mg theoretical, 208%). LC-MS m/z 378.4 (M+1).

Example 161

(S,Z)-5-((2-(3-aminopiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and (S)-tert-butylpiperidin-3-ylcarbamate. The crude protected amine was then treated with2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removedunder reduced pressure (Genevac HT-4) and the crude residues werepurified using reverse phase HPLC (MS-triggered fraction collection)with an acetonitrile/water or methanol/water gradient andtrifluoroacetic acid as a modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) (46.8 mg, 30.2 mgtheoretical, 155%). LC-MS m/z 306.1 (M+1).

Example 162

(R,Z)-5-((2-(3-aminopiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and (R)-tert-butylpiperidin-3-ylcarbamate. The crude protected amine was then treated with2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removedunder reduced pressure (Genevac HT-4) and the crude residues werepurified using reverse phase HPLC (MS-triggered fraction collection)with an acetonitrile/water or methanol/water gradient andtrifluoroacetic acid as a modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) (44.2 mg, 30.2 mgtheoretical, 146%). LC-MS m/z 306.1 (M+1).

Example 163

(Z)-5-β6-(methyl(piperidin-3-yl)amino)-2-(piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using General Procedure 2 for the Preparation ofAmino-Analogs (Example 81) using tert-butyl3-(methylamino)piperidine-1-carboxylate and piperidine (11.4 mg, 54.0 mgtheoretical, 21.1%). LC-MS m/z 403.2 (M+1).

Example 164

(Z)-5-((2-(methyl(piperidin-3-yl)amino)-6-(piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using General Procedure 2 for the Preparation ofAmino-Analogs (Example 81) using piperidine and tert-Butyl3-(methylamino)piperidine-1-carboxylate (10.5 mg, 26.3 mg theoretical,41.9%). LC-MS m/z 403.2 (M+1).

Example 165

(Z)-5-((2,6-di(piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using General Procedure 2 for the Preparation ofAmino-Analogs (Example 81) using piperidine (14.0 mg, 233 mgtheoretical, 6%). LC-MS m/z 374.2 (M+1).

Example 166

(Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared as follows.

4-Methyl-2-(methylthio)-6-(trifluoromethyl)pyrimidine

A 30 mL round-bottomed vial was charged with1,1,1-trifluoropentane-2,4-dione (2.00 g, 13.0 mmol, 1 equiv.), ethanol(15 mL, 0.8 M), thiomethylisourea hemi sulfuric acid salt (1.807 g, 6.5mmol, 1 equiv.) and the reaction mixture was shaken at 80° C. for 3 h.The solvent was concentrated under reduced pressure and the residue waspartitioned between CH₂Cl₂ (25 mL) and saturated NaHCO₃ (25 mL). Theaqueous layer was extracted with EtOAc (2×10 mL) and the combinedorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure to provide the crude desired pyrimidine as a slightly orangesolid. Purification using the Biotage (SiO₂, 25 g cartridge,Hexanes/EtOAc 95:5 to 75:25) afforded 1.66 g of the pure desired product(2.70 g theoretical, 61.4%). LC-MS m/z 209 (M+1).

(Z)-5-((2-(Methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione

A 30 mL round-bottomed vial was charged with4-methyl-2-(methylthio)-6-(trifluoromethyl)pyrimidine (0.500 g, 2.4mmol, 1 equiv.), ethanol (5 mL, 0.48 M), selenium dioxide (0.293 mg, 2.6mmol, 1.1 equiv.), and the reaction mixture was shaken at 90° C. for 40h and then RT for 14 d. The crude reaction mixture was then treated withthiazolidine-2,4-dione (0.281 g, 2.4 mmol, 1 equiv.), triethylamine (1.0mL, 7.20 mmol, 3 equiv.) and the reaction mixture was shaken for 16 h at80° C. The solvent was concentrated under reduced pressure and theresidue was partitioned between EtOAc (30 mL) and saturated NaHCO₃ (25mL). The aqueous layer was extracted with EtOAc (2×10 mL) and thecombined organic layer was dried over Na₂SO₄ and concentrated underreduced pressure. The crude product was purified using the Biotage(SiO₂, 10 g cartridge, CH₂Cl₂/MeOH 99:1 to 9:1) that afforded 270 mg ofpartially purified product that was re-purified using the Biotage (SiO₂,10 g cartridge, Hexanes/EtOAc 90:10 to 0:1 then CH₂Cl₂/MeOH 99:1 to 9:1)afforded 212 mg of yellow solid that was still not completely pure butwas used directly in the next step without further purification.

(Z)-5-((2-(Methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione

An 8 mL round-bottomed vial was charged with the pyrimidine sulfide (212mg, 0.66 mmol, 1 equiv.), CH₂Cl₂ (3 mL, 0.22 M), m-CPBA 50% by weight(0.683 g, 1.98 mmol, 3 equiv.) was added over a 1 min. period at RT.After 3.5 h, an additional 3 equivalents of m-CPBA 50% by weight (0.683g, 1.98 mmol, 3 equiv.) was added and the reaction mixture was stirredat RT overnight. The resulting white solid was filtered and washed withCH₂Cl₂ and then with Et₂O to provide 67 mg of an off-white solid (233 mgtheoretical, 28.7%), which was used in the next step without furtherpurification. LC-MS m/z 354 (M+1).

(Z)-tert-Butyl((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)methyl)carbamate

An 8 mL round-bottomed vial was charged with the 2-sulfone pyrimidine(67 mg, 0.19 mmol, 1 equiv.), DMSO (1 mL, 0.19M), tert-Butyl(piperidin-4-ylmethyl)carbamate (40.6 mg, 0.19 mmol, 1 equiv.), DIPEA(66 μL, 0.38 mmol, 2 equiv.), and the reaction mixture was stirred for 1h at RT and then 50° C. for 3 h. The reaction was directly purifiedusing reverse phase HPLC (2 injections of 500 μL, 12 min method,methanol/water gradient with 0.4% TFA) to afford the desired product(15.3 mg, 92.7 mg theoretical, 16.5%).

(Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione

An 8 mL round-bottomed vial was charged with the CF₃-pyrimidine (15.3mg, 0.031 mmol, 1 equiv.), CH₂Cl₂ (1 mL, 0.03 M), TFA (0.5 mL, 6.5 mmol,208 equiv.), and the reaction mixture was stirred for 1 h at RT. Thesolvent was concentrated under reduced pressure and the residue wasdried under high vacuum. The residue was washed with ether (2×2 mL) andthe yellow solid was dried under high vacuum overnight to afford (13.4mg, 15.8 mg theoretical, 85%). LC-MS m/z 388.1 (M+1).

Example 167

(Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared as follows.

Methyl 2-chloro-6-methoxypyrimidine-4-carboxylate

A 30 mL round-bottomed vial was charged with methyl2,6-dichloropyrimidine-4-carboxylate (0.6 g, 2.9 mmol, 1 equiv.),methanol (6 mL, 0.97 M), K₂CO₃ (0.401 g, 2.9 mmol, 1 equiv.), and thereaction mixture was shaken at 65° C. for 1.5 h. The solvent wasconcentrated under reduced pressure and the residue was partitionedbetween EtOAc (25 mL) and H₂O (25 mL) and the water layer was extractedwith EtOAc (2×20 mL). The combined organic layer was dried over Na₂SO₄and concentrated under reduced pressure to provide the crudechloropyrimidine (441 mg, 588 mg theoretical, 75%), which was used inthe next step without further purification.

Methyl2-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-6-methoxypyrimidine-4-carboxylate

An 8 mL round-bottomed vial was charged with the 2-chloropyrimidine (150mg, 0.74 mmol, 1.5 equiv.), methanol (1.5 mL, 0.49 M), tert-Butyl(piperidin-4-ylmethyl)carbamate (159 mg, 0.49 mmol, 1 equiv.), DIPEA(258 μL, 0.99 mmol, 2 equiv.), and the reaction mixture was shaken at65° C. for 3 h. The solvent was concentrated under reduced pressure andthe residue was partitioned between EtOAc (25 mL) and saturated NaHCO₃(10 mL). The organic layer was dried over Na₂SO₄ and dried under reducedpressure to provide the crude product. Purification using the Biotage(SiO₂, 10 g cartridge, Hexanes/EtOAc 95:5 to 40:60) afforded the desiredpyrimidine intermediate as a white solid (219 mg, 281 mg theoretical,78%).

tert-Butyl((1-(4-formyl-6-methoxypyrimidin-2-yl)piperidin-4-yl)methyl)carbamate

A 50 mL 2-neck round-bottomed flask was charged with the methyl esterintermediate (150 mg, 0.39 mmol, 1 equiv.), CH₂Cl₂ (2 mL, 0.195 M), andthen DIBAL-H 1 M in CH₂Cl₂ (0.59 mL, 0.59 mmol, 1.5 equiv.) was addedover a 4 minute period at −78° C. The reaction was then stirred for 1.5h at −78° C. and for 1.5 h between −78° C. and RT. LC-MS showed mostlystarting material so the reaction mixture was re-cooled to −78° C. andDIBAL-H (0.8 mL, 0.8 mmol, 2 equiv.) was added. LC-MS showed mostlystarting material. The reaction mixture was stored at −20° C. for 3 d.The reaction mixture was cooled to −78° C. and treated with 1M DIBAL-Hin hexanes (0.59 mL, 0.59 mmol, 1 equiv.) over a 5 min. period, whichproduced a white precipitate. After 2.5 h, another equivalent of DiBAL-H(1 M in Hexanes, 0.59 mL) was added over a 15 min. period at −78° C. Thereaction was quenched at −78° C. after 35 min. with methanol (1 mL). Thesolvent were concentrated under reduced pressure and the residue waspartitioned between CH₂Cl₂ (20 mL) and saturated NaHCO₃ (20 mL). Theorganic layer was dried over Na₂SO₄ and the solvent was concentratedunder reduced pressure to provide the crude product, which was used inthe next step without further purification.

(Z)-tert-Butyl((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-methoxypyrimidin-2-yl)piperidin-4-yl)methyl)carbamate

An 8 mL round-bottomed vial was charged with the crude aldehyde (0.2mmol, estimated), ethanol (2 mL), thiazolidine-2,4-dione (23 mg, 0.2mmol, 1 equiv.), triethylamine (56 μL, 0.4 mmol, 2 equiv.), purged withAr, and the reaction mixture was shaken at 80° C. for 24 h. The crudemixture was purified using the Biotage (SiO₂, 10 g cartridge,CH₂Cl₂/MeOH 99:1 to 94:6) afforded 113 mg of the partially purifiedproduct. The sample was re-purified using reverse phase HPLC(methanol/water 10-90%, 0.4% TFA, 3 equal injections) provided the pureproduct as a TFA salt (47.3 mg, 225 mg theoretical, 21%). LC-MS m/z 450(M+1).

(Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione

An 8 mL round-bottomed vial was charged with the MeO-pyrimidine bocprotected amine (47.3 mg, 105 μmol, 1 equiv.), CH₂Cl₂ (1.3 mL, 0.08 M),TFA (0.5 mL, 6.5 mmol, 62 equiv.), and the reaction mixture was stirredfor 1 h at RT. The solvents were concentrated under reduced pressure andthe residue was re-dissolved in DMSO (0.9 mL) and purified by reversephase HPLC (methanol/water with 0.4% TFA, 10-90% method, 2 injections of500 μL) to provide as the TFA salt (43.9 mg, 48.8 mg theoretical, 90%).LC-MS m/z 350.1 (M+1).

Example 168 Synthesized Pyridine Analogs

(Z)-5-((6-(piperidin-1-yl)pyridin-2-yl)methylene)thiazolidine-2,4-dionewas prepared as follows.

A 30 mL round-bottomed vial was charged with thiazolidine-2,4-dione (300mg, 2.56 mmol, 1 equiv.), toluene (5 mL, 0.5 M), 6-bromopicolinaldehyde(477 mg, 2.56 mmol, 1 equiv.), glacial acetic acid (22 μL, 0.256 mmol,0.1 equiv.), piperidine (25 μL, 0.256 mmol, 0.1 equiv.), purged with Ar,and heated with shaking at 125° C. After heating for 16 h, the yellowreaction solution was pipeted away from the solid precipitate. Theprecipitate was washed with acetone (3×5 mL) and dried under high vacuumto afford the desired product as a solid (439 mg, 731 mg theoretical,60%), which was used in the next step without further purification.

A 2 dram round-bottomed vial was charged with(Z)-5-((6-bromopyridin-2-yl)methylene)thiazolidine-2,4-dione (60 mg,0.210 mmol, 1 equiv.), DMSO (1 mL, 0.08 M), diisopropylethylamine (34μL, 0.2 mmol, 1 equiv.), and piperidine (21 μL, 0.21 mmol, 1 equiv.),and the reaction was heated with shaking at 110° C. for 24 h. Thesolvent was removed under reduced pressure (Genvac HT-4) and the cruderesidue was purified using reverse phase HPLC (MS-triggered fractioncollection) with an acetonitrile/water gradient and trifluoroacetic acidas a modifier. The pure fractions were then concentrated under reducedpressure (Genevac HT-4) to provide(Z)-5-((6-(piperidin-1-yl)pyridin-2-yl)methylene)thiazolidine-2,4-dione(7.9 mg, 60.9 mg theoretical, 12.9%). LC-MS m/z 290.1 (M+1).

Example 169 Synthesized Reductive Amination Analogs

General Reductive Amination Procedure:

A 2-dram round-bottomed vial was charged with the crude amine/TFA saltprepared using the general displacement procedure followed by thegeneral TFA de-protection procedure (0.115 mmol), DCE (2 mL), DIPEA (6eq. 0.690 mmol), DMF (1 mL), the aldehyde (1 equiv., 0.115 mmol), andthe reaction mixture was shaken for 1 h at RT. The reaction mixture wasthen treated with NaBH(OAc)₃ (2.5 equiv., 0.230 mmol) and the reactionwas shaken 16 h at RT. The reaction mixture was then diluted with DCE (2mL) and NaHCO₃ (2 mL). The aqueous layer was back extracted with DCE(2×2 mL) and the combined organic layer was concentrated under reducedpressure (Genevac HT-4) and the crude residue was purified using reversephase HPLC (MS-triggered fraction collection) with an acetonitrile/wateror methanol/water gradient and trifluoroacetic acid as the modifier. Thepure fractions were then concentrated under reduced pressure (GenevacHT-4) to afford the pure products as the TFA salt.

Example 170

(Z)-5-((2-((2-(dimethylamino)ethyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and picolinaldehyde (16.1 mg, 47 mg theoretical, 34.3%). LC-MS m/z448.5 (M+1).

Example 171

(Z)-5-((2-((2-((3-chlorobenzyl)amino)ethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general General Reductive Amination Procedure(Example 169) and 3-chlorobenzaldehyde (5.6 mg, 40.9 mg theoretical,13.7%). LC-MS m/z 390.8 (M+1).

Example 172

(Z)-5-((2-(4-(((pyridin-2-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and picolinaldehyde (8.5 mg, 71.8 mg theoretical, 11.8%). LC-MS m/z411.5 (M+1).

Example 173

(S,Z)-5-((2-((1-(pyridin-2-ylmethyl)piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and picolinaldehyde (2.6 mg, 34.7 mg theoretical, 7.1%). LC-MS m/z397.1 (M+1).

Example 174

(Z)-5-((2-(4-((((6-methylpyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 6-methylpicolinaldehyde (10.4 mg, 74.3 mg theoretical, 14%).LC-MS m/z 425.5 (M+1).

Example 175

(Z)-5-((2-(4-((bis((6-methylpyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 6-methylpicolinaldehyde (2.5 mg, 92.6 mg theoretical, 2.7%).LC-MS m/z 530.6 (M+1).

Example 176

(Z)-5-((2-(4-(((pyridin-3-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and nicotinaldehyde (5.3 mg, 71.8 mg theoretical, 7.4%). LC-MS m/z411.5 (M+1).

Example 177

(Z)-5-((2-(4-(((pyridin-4-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and isonicotinaldehyde (4.1 mg, 71.8 mg theoretical, 5.7%). LC-MSm/z 411.5 (M+1).

Example 178

(S,Z)-5-((2-((1-(quinolin-2-ylmethyl)piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and quinoline-2-carbaldehyde (2.2 mg, 78 mg theoretical, 2.8%).LC-MS m/z 447.5 (M+1).

Example 179

(S,Z)-5-((2-((1-(isoquinolin-3-ylmethyl)piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and isoquinoline-3-carbaldehyde (1.5 mg, 78 mg theoretical, 1.9%).LC-MS m/z 447.5 (M+1).

Example 180

(Z)-5-((2-(4-(((quinolin-2-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and quinoline-2-carbaldehyde (3.8 mg, 81 mg theoretical, 4.7%).LC-MS m/z 461.5 (M+1).

Example 181

(Z)-5-((2-(4-((((2-methylquinolin-4-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 2-methylquinoline-4-carbaldehyde (35.1 mg, 56.5 mg theoretical,62.2%). LC-MS m/z 475.5 (M+1).

Example 182

(Z)-5-((2-(4-(((isoquinolin-1-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and isoquinoline-1-carbaldehyde (35.1 mg, 43.8 mg theoretical,80%). LC-MS m/z 461.5 (M+1).

Example 183

(Z)-5-((2-(4-((((6-methoxypyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 6-methoxypicolinaldehyde (37.5 mg, 52.4 mg theoretical, 71.5%).LC-MS m/z 441.5 (M+1).

Example 184

(Z)-5-((2-(4-((((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 5-(trifluoromethyl)picolinaldehyde (23 mg, 56.9 mg theoretical,40.4%). LC-MS m/z 479.5 (M+1).

Example 185

(Z)-5-((2-(4-((((6-fluoropyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 6-fluoropicolinaldehyde (29.3 mg, 51 mg theoretical, 57.5%).LC-MS m/z 429.5 (M+1).

Example 186

(Z)-5-((2-(4-((((2-(piperidin-1-yl)pyrimidin-5-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 2-(piperidin-1-yl)pyrimidine-5-carbaldehyde (40.1 mg, 47 mgtheoretical, 80%). LC-MS m/z 495.5 (M+1).

Example 187

(Z)-5-((2-(4-((((3-(trifluoromethyl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 3-(trifluoromethyl)picolinaldehyde (44 mg, 45.5 mg theoretical,97%). LC-MS m/z 479.5 (M+1).

Example 188

(Z)-5-((2-(4-((((3-fluoropyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 3-fluoropicolinaldehyde (42.5 mg, 40.7 mg theoretical, 104%).LC-MS m/z 429.5 (M+1).

Example 189

(Z)-5-((2-(4-((((8-methoxyquinolin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 8-methoxyquinoline-2-carbaldehyde (35.5 mg, 46.6 mgtheoretical, 76%). LC-MS m/z 491.5 (M+1).

Example 190

(Z)-5-((2-(4-((((8-fluoroquinolin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 8-fluoroquinoline-2-carbaldehyde (28.5 mg, 45.5 mg theoretical,62.7%). LC-MS m/z 479.5 (M+1).

Example 191

(Z)-5-((2-(4-((((6-fluoroquinolin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 6-fluoroquinoline-2-carbaldehyde (32.7 mg, 45.5 mg theoretical,71.9%). LC-MS m/z 479.5 (M+1).

Example 192

(Z)-5-((2-(4-((pyridin-2-ylamino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 2-chloroisonicotinaldehyde (19.6 mg, 42.3 mg theoretical,46.4%). LC-MS m/z 445.5 (M+1).

Example 193

(Z)-5-((2-(4-((((5-fluoropyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 5-fluoropicolinaldehyde (7.9 mg, 40.7 mg theoretical, 19.4%).LC-MS m/z 429.5 (M+1).

Example 194

(Z)-5-((2-(4-(((quinolin-4-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and quinoline-4-carbaldehyde (24.6 mg, 43.8 mg theoretical, 56.2%).LC-MS m/z 461.5 (M+1).

Example 195

(Z)-5-((2-(4-((((1,8-naphthyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 1,8-naphthyridine-2-carbaldehyde (6.9 mg, 43.8 mg theoretical,15.7%). LC-MS m/z 462.5 (M+1).

Example 196

(S,Z)-5-((2-(3-((quinolin-2-ylmethyl)amino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and quinoline-2-carbaldehyde (30.9 mg, 54.9 mg theoretical, 56.3%).LC-MS m/z 447.2 (M+1).

Example 197

(S,Z)-5-((2-(3-(((6-fluoroquinolin-2-yl)methyl)amino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 6-fluoroquinoline-2-carbaldehyde (26.7 mg, 57.1 mg theoretical,46.7%). LC-MS m/z 465.5 (M+1).

Example 198

(S,Z)-5-((2-(3-(((8-methoxyquinolin-2-yl)methyl)amino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 8-methoxyquinoline-2-carbaldehyde (16.4 mg, 58.6 mgtheoretical, 28%). LC-MS m/z 477.5 (M+1).

Example 199

(R,Z)-5-((2-(3-((quinolin-2-ylmethyl)amino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169)e and quinoline-2-carbaldehyde (24.9 mg, 54.9 mg theoretical,45.3%). LC-MS m/z 447.5 (M+1).

Example 200

(R,Z)-5-((2-(3-(((6-fluoroquinolin-2-yl)methyl)amino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 6-fluoroquinoline-2-carbaldehyde (24.1 mg, 57.1 mg theoretical,42.2%). LC-MS m/z 465.5 (M+1).

Example 201

(R,Z)-5-((2-(3-(((8-methoxyquinolin-2-yl)methyl)amino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 8-methoxyquinoline-2-carbaldehyde (15.5 mg, 58.6 mgtheoretical, 26.4%). LC-MS m/z 477.5 (M+1).

Example 202

(R,Z)-5-((2-(3-(((2-methylquinolin-4-yl)methyl)amino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 2-methylquinoline-4-carbaldehyde (25 mg, 56.6 mg theoretical,44.1%). LC-MS m/z 461.5 (M+1).

Example 203

(S,Z)-5-((2-(3-(((2-methylquinolin-4-yl)methyl)amino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 2-methylquinoline-4-carbaldehyde (30 mg, 56.6 mg theoretical,53%). LC-MS m/z 461.5 (M+1).

Example 204

(Z)-5-((2-(4-((((6-(4-fluorophenyl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 6-(4-fluorophenyl)picolinaldehyde (26.5 mg, 36.3 mgtheoretical, 72.9%). LC-MS m/z 505.5 (M+1).

Example 205

(Z)-5-((2-(4-((((6-(thiophen-2-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 6-(thiophen-2-yl)picolinaldehyde (15.2 mg, 35.5 mg theoretical,42.9%). LC-MS m/z 493.5 (M+1).

Example 206

(Z)-5-((2-(4-((((6-(benzo[d][1,3]dioxol-5-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 6-(benzo[d][1,3]dioxol-5-yl)picolinaldehyde (25.8 mg, 38.2 mgtheoretical, 67.5%). LC-MS m/z 531.5 (M+1).

Example 207

(Z)-5-((2-(4-((((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and 6-(thiophen-3-yl)picolinaldehyde (32.5 mg, 35.5 mg theoretical,92%). LC-MS m/z 493.5 (M+1).

Example 208

(Z)-5-((2-(4-(((azetidin-2-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and tert-butyl 2-formylazetidine-1-carboxylate followed by thegeneral TFA de-protection procedure (15.2 mg, 68 mg theoretical, 22.4%).LC-MS m/z 389.5 (M+1).

Example 209

(Z)-5-((2-(4-(((pyrrolidin-3-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and tert-butyl 3-formylpyrrolidine-1-carboxylate followed by thegeneral TFA de-protection procedure (17.1 mg, 70.4 mg theoretical, 24%).LC-MS m/z 403.5 (M+1).

Example 210

(Z)-5-((2-(((3S)-1-(pyrrolidin-3-ylmethyl)piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and tert-butyl 3-formylpyrrolidine-1-carboxylate followed by thegeneral TFA de-protection procedure (2.7 mg, 34.0 mg theoretical, 7.9%).LC-MS m/z 389.2 (M+1).

Example 211

(Z)-5-((2-(4-(((piperidin-3-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination

Procedure (Example 169) and tert-butyl 3-formylpiperidine-1-carboxylatefollowed by the general TFA de-protection procedure (26.5 mg, 72.9 mgtheoretical, 36.4%). LC-MS m/z 417.2 (M+1).

Example 212

(Z)-5-((2-(((3S)-1-(azetidin-2-ylmethyl)piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and tert-butyl 2-formylazetidine-1-carboxylate followed by thegeneral TFA de-protection procedure (2.2 mg, 32.8 mg theoretical, 6.0%).LC-MS m/z 375.2 (M+1).

Example 213

(Z)-5-((2-(((3S)-1-(piperidin-3-ylmethyl)piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reductive Amination Procedure (Example169) and tert-butyl 3-formylpiperidine-1-carboxylate followed by thegeneral TFA de-protection procedure (4.5 mg, 35.3 mg theoretical,11.9%). LC-MS m/z 403.2 (M+1).

Example 214

General Reverse Reductive Amination Procedure:

A 2-dram round-bottomed vial was charged with tert-butyl4-formylpiperidine-1-carboxylate (0.7 mmol), the amine (1 equiv., 0.7mmol), DCE (3 mL), and shaken for 1 h at RT. The reaction mixture wasthen treated with NaBH(OAc)₃ (2 equiv., 1.4 mmol) and shaken for 16 h atRT. The reaction mixture was then washed with saturated NaHCO₃ (3 mL)and the aqueous layer was back extracted with DCE (2×2 mL. The combinedorganic layer was concentrated under reduced pressure (GeneVac HT-4) andthe crude residue was purified by HPLC using a MeOH/H₂O gradient withTFA as the modifier. The resulting Boc-protected piperidine analog wastreated with DCE (3 mL), TFA (0.5 mL), and shaken at RT for 2 h. Thereaction mixture was concentrated under reduced pressure (GeneVac HT-4)and used in the general displacement procedure without furtherpurification.

Example 215

(Z)-5-((2-(4-((pyridin-3-ylamino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reverse Reductive Amination Procedure(Example 214) and pyridin-3-amine (15.5 mg, 41.7 mg theoretical, 37.2%).LC-MS m/z 397.5 (M+1).

Example 216

(Z)-5-((2-(4-(((4-morpholinophenyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reverse Reductive Amination Procedure(Example 214) and 4-morpholinoaniline (12.5 mg, 50.5 mg theoretical,24.7%). LC-MS m/z 481.5 (M+1).

Example 217

(Z)-5-((2-(4-((pyridin-2-ylamino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reverse Reductive Amination Procedure(Example 214) and pyridin-2-amine (21.2 mg, 41.7 mg theoretical, 50.9%).LC-MS m/z 397.5 (M+1).

Example 218

(Z)-5-((2-(4-((((1H-benzo[d]imidazol-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reverse Reductive Amination Procedure(Example 214) and (1H-benzo[d]imidazol-2-yl)methanamine (8 mg, 42.7 mgtheoretical, 18.7%). LC-MS m/z 450.5 (M+1).

Example 219

(Z)-5-((2-(4-((quinolin-2-ylamino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the General Reverse Reductive Amination Procedure(Example 214) and quinolin-2-amine (21.2 mg, 128 mg theoretical,16.53%). LC-MS m/z 447.5 (M+1).

Example 220

(Z)—N-(1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)pyrrolidin-3-yl)furan-2-carboxamidewas prepared as follows.

A 2-dram round-bottomed vial was charged with(Z)-5-(2-(3-aminopyrrolidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione,prepared using the general displacement procedure followed by thegeneral TFA de-protection procedure, (25 mg, 0.065 mmol), DCM (1 mL),furan-2-carbonyl chloride (8 μL, 0.082 mmol, 1.3 equiv.), and pyridine(0.040 mL, 0.491 mmol, 7.5 equiv.). The reaction mixture was shaken atRT for 16 h, the solvent was removed under reduced pressure (GenevacHT-4), and the crude residue was purified using reverse phase HPLC(MS-triggered fraction collection) with an acetonitrile/water gradientand trifluoroacetic acid as the modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) to provide the titlecompound (2.7 mg, 33.1 mg theoretical, 8.2%). LC-MS m/z 386.1 (M+1).

Example 221

(Z)-5-((2-(4-(furan-2-carbonyl)-1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared as follows.

A 2-dram round-bottomed vial was charged with(Z)-5-((2-(1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione,prepared using the general displacement procedure followed by thegeneral TFA de-protection procedure, (25 mg, 0.062 mmol), DCM (1 mL),furan-2-carbonyl chloride (8.07 μL, 0.062 mmol, 1 equiv.), and pyridine(0.040 mL, 0.491 mmol, 8 equiv.). The reaction mixture was shaken at RTfor 16 h, the solvent was removed under reduced pressure (Genevac HT-4),and the crude residue was purified using reverse phase HPLC(MS-triggered fraction collection) with an acetonitrile/water gradientand trifluoroacetic acid as the modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) to provide the titlecompound (1.9 mg, 32.7 mg theoretical, 5.8%). LC-MS m/z 400.1 (M+1).

Example 222

(Z)—N-((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)pyrazine-2-carboxamidewas prepared as follows.

A 2-dram round-bottomed vial was charged with(Z)-5-(2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione,prepared using the general displacement procedure followed by thegeneral TFA de-protection procedure, (56 mg, 0.175 mmol), DCM (3 mL),pyrazine-2-carbonyl chloride (25 mg, 0.175 mmol, 1 equiv.), and pyridine(0.120 mL, 1.47 mmol, 8.4 equiv.). The reaction mixture was shaken at RTfor 16 h, the solvent was removed under reduced pressure (Genevac HT-4),and the crude residue was purified using reverse phase HPLC(MS-triggered fraction collection) with an acetonitrile/water gradientand trifluoroacetic acid as the modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) to provide the titlecompound (4.9 mg, 74.5 mg theoretical, 6.6%). LC-MS m/z 426.5 (M+1).

Example 223

(Z)—N-((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)-2,2,2-trifluoroacetamidewas prepared as follows.

A 2-dram round-bottomed vial was charged with(Z)-5-(2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione,prepared using the general displacement procedure followed by thegeneral TFA de-protection procedure, (56 mg, 0.175 mmol), DCM (3 mL),2,2,2-trifluoroacetyl chloride (23 mg, 0.175 mmol, 1 equiv.), andpyridine (0.120 mL, 1.47 mmol, 8.4 equiv.). The reaction mixture wasshaken at RT for 16 h, the solvent was removed under reduced pressure(Genevac HT-4), and the crude residue was purified using reverse phaseHPLC (MS-triggered fraction collection) with an acetonitrile/watergradient and trifluoroacetic acid as the modifier. The pure fractionswere then concentrated under reduced pressure (Genevac HT-4) to providethe title compound (6.5 mg, 72.7 mg theoretical, 8.9%). LC-MS m/z 416.1(M+1).

Example 224

(S,Z)-5-((2-((1-(pyrazine-2-carbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared as follows.

A 2-dram round-bottomed vial was charged with(S,Z)-5-((2-(piperidin-3-ylamino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione,prepared using the general displacement procedure followed by thegeneral TFA de-protection procedure, (27 mg, 0.088 mmol), DCM (2 mL),pyrazine-2-carbonyl chloride (12.5 mg, 0.088 mmol, 1 equiv.), andpyridine (0.080 mL, 0.982 mmol, 11 equiv.). The reaction mixture wasshaken at RT for 16 h, the solvent was removed under reduced pressure(Genevac HT-4), and the crude residue was purified using reverse phaseHPLC (MS-triggered fraction collection) with an acetonitrile/watergradient and trifluoroacetic acid as the modifier. The pure fractionswere then concentrated under reduced pressure (Genevac HT-4) to providethe title compound (2.6 mg, 36.1 mg theoretical, 6.4%). LC-MS m/z 412.1(M+1).

Example 225

(Z)-3-amino-3-(1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)-N-(3-(trifluoromethoxy)benzyl)propanamidewas prepared as follows.

A 2-dram round-bottomed vial was charged with(Z)-3-((tert-butoxycarbonyl)amino)-3-(1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)propanoicacid, prepared using the general displacement procedure, (25 mg, 0.052mmol), DMF (1 mL), DIPEA (34.9 μL, 0.209 mmol, 4 equiv.), and(3-(trifluoromethoxy)phenyl)methanamine (7.85 μL, 0.052 mmol, 1 equiv.).The reaction mixture was shaken for 20 minutes then HBTU (29.8 mg, 0.079mmol, 1.5 equiv.) was added and the reaction mixture was shaken at RTfor 3 h. The solvent was removed under reduced pressure (Genevac HT-4)and the resulting solid was washed with water (2×1 mL) and dried underhigh vacuum to provide 20 mg of (Z)-tert-butyl(1-(1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)-3-oxo-3-(3-(trifluoromethoxy)benzyl)amino)propyl)carbamate(20 mg, 34.1 mg theoretical, 58.7%).

A 2-dram round-bottomed vial was charged with (Z)-tert-butyl(1-(1-(4-(2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)-3-oxo-3-((3-(trifluoromethoxy)benzyl)amino)propyl)carbamate(20 mg, 0.031 mmol), DCM (0.5 mL), and TFA (0.5 mL). The reactionmixture was shaken at RT for 16 h. The solvent was removed under reducedpressure (Genevac HT-4) and the crude residue was purified using reversephase HPLC (MS-triggered fraction collection) with an acetonitrile/watergradient and trifluoroacetic acid as the modifier. The pure fractionswere then concentrated under reduced pressure (Genevac HT-4) to providethe title compound (15.6 mg, 16.9 mg theoretical, 92%). LC-MS m/z 551.2(M+1)

Example 226

(Z)-methyl2-(((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)amino)pyrimidine-4-carboxylatewas prepared as follows.

Methyl 2-((piperidin-4-ylmethyl)amino)pyrimidine-4-carboxylate wasprepared as follows: A 40 mL round-bottomed vial was charged withtert-butyl 4-(aminomethyl)piperidine-1-carboxylate (1.76 mmol, 1.1equiv.), acetonitrile (4 mL), DiPEA (2.37 mmol, 1.5 equiv.), methyl2,6-dichloropyrimidine-4-carboxylate (1.58 mmol, 1 equiv.), and thenshaken at 85° C. for 72 h. The reaction mixture was concentrated underreduced pressure and purified on SiO₂ using a Biotage and a 10-50%EtOAc/hexanes gradient to provide the desired protected amine (233 mg,552 mg theoretical, 42%). Methyl2-((piperidin-4-ylmethyl)amino)pyrimidine-4-carboxylate was preparedusing the general TFA de-protection procedure and used directly in thegeneral displacement procedure to provide the title compound (4 mg, 73.4mg theoretical, 5%). LC-MS m/z 456.1 (M+1).

Example 227

(Z)-5-((2-(4-((imidazo[1,2-b]pyridazin-6-ylamino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using a procedure similar to the procedure used in thesynthesis of Example 226 to provide the title compound (12.2 mg, 45.9 mgtheoretical, 26.6%). LC-MS m/z 437.5 (M+1).

Example 228

(Z)-5-((2-(4-(((1H-benzo[d]imidazol-2-yl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using a procedure similar to the procedure used in thesynthesis of Example 226 to provide the title compound (21.4 mg, 45.8 mgtheoretical, 46.7%). LC-MS m/z 436.5 (M+1).

Example 229

(Z)-5-((2-(4-(((7H-purin-6-yl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using a procedure similar to the procedure used in thesynthesis of Example 226 to provide the title compound (12.7 mg, 41.6 mgtheoretical, 30.6%). LC-MS m/z 438.5 (M+1).

Example 230

General Procedure for the Preparation of Sulfonamides

A 2-dram round-bottomed vial was charged with the appropriate sulfonylchloride (0.072 mmol, 1 equiv.) in 0.5 mL of DMF, and then treatedcarefully with a solution of the appropriate amine intermediate,prepared using the general displacement procedure followed by thegeneral TFA de-protection procedure, (0.072 mmol, 1 equiv.), DIPEA(0.288 mmol, 4 equiv.), and 1 mL of DMF. The reaction mixture was thenshaken at room temperature overnight. The reaction mixture waspartitioned between 2 mL DCE and 1 mL sat. NaHCO₃ and the aqueous layerwas extracted with DCE (2×2 mL). The combined organic layer was theconcentrated under reduced pressure (Genevac HT-4) and the crude residuewas purified using reverse phase HPLC (MS-triggered fraction collection)with an acetonitrile/water or methanol/water gradient andtrifluoroacetic acid as the modifier. The pure fractions were thenconcentrated under reduced pressure (Genevac HT-4) to afford thesulfonamide analogs.

Example 231

(Z)—N-((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)naphthalene-2-sulfonamidewas prepared using a procedure similar to the general proceduredescribed in Example 230 to provide the title compound (7.7 mg, 36.7 mgtheoretical, 21%). LC-MS m/z 510.5 (M+1).

Example 232

(Z)—N-((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)-6-methoxynaphthalene-2-sulfonamidewas prepared using a procedure similar to the general proceduredescribed in Example 230 to provide the title compound (15.2 mg, 38.9 mgtheoretical, 39.1%). LC-MS m/z 540.5 (M+1).

Example 233

(Z)-5-chloro-N-((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)naphthalene-2-sulfonamidewas prepared using a procedure similar to the general proceduredescribed in Example 230 to provide the title compound (9.2 mg, 39.2 mgtheoretical, 23.5%). LC-MS m/z 545 (M+1).

Example 234

(Z)—N-((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)-1-methyl-1H-indole-5-sulfonamidewas prepared using a procedure similar to the general proceduredescribed in Example 230 to provide the title compound (13.2 mg, 36.9 mgtheoretical, 35.8%). LC-MS m/z 513.5 (M+1).

Example 235

Protocols for Kinase Activity Screening for CK1γ1(h), CK1γ2(h),CK1γ3(h), CK1δ(h) and CK1(y): Kinase screening was performed byMillipore UK Ltd. Kinase dilution buffer composition: 20 mM MOPS, 1 mMEDTA, 0.01% Brij-35, 5% Glycerol, 0.1% b-mercaptoethanol, 1 mg/mL BSA.

TABLE 4 Kinase assay ATP concentration within 15 μM of K_(M). KinaseK_(M) (μM) CK1γ1(h) 15 CK1γ2(h) 10 CK1γ3(h) 10 CK1δ(h) 70 CK1(y) 45

In a final reaction volume of 25 μL, the compound of interest (at thedesired concentration) and the appropriate kinase (5-10 mU) wereincubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 200 μM KRRRALS(p)VASLPGL(SEQ ID NO:1), 10 mM magnesium acetate and [γ-³³P-ATP] (specificactivity approx. 500 cpm/pmol, concentration as required). The reactionwas initiated by the addition of the MgATP mix. After incubation for 40minutes at room temperature, the reaction was stopped by the addition of5 μL of a 3% phosphoric acid solution. 10 μL of the reaction mixture wasthen spotted onto a P30 filtermat; and washed three times for 5 minutesin 75 mM phosphoric acid, and once in methanol prior to drying andscintillation counting. The estimated IC₅₀ values for several compoundsare provided in Table 5.

TABLE 5 Estimated IC₅₀ values Compound Kinase IC₅₀ (nM) 4981 CK1γ1(h)121 4981 CK1γ2(h) 19 4981 CK1γ3(h) 401 4981 CK1δ(h) >10,000 4981CK1(y) >10,000 4993 CK1γ1(h) 5,034 4993 CK1γ2(h) 716 4993 CK1γ3(h) 3,1684993 CK1δ(h) >10,000 4993 CK1(y) 9,853 4991 CK1γ1(h) 571 4991 CK1γ2(h)146 4991 CK1γ3(h) 1,085 4991 CK1δ(h) >10,000 4991 CK1(y) 1,161 4999CK1γ1(h) 163 4999 CK1γ2(h) 37 4999 CK1γ3(h) 470 4999 CK1δ(h) 3,446 4999CK1(y) 2,990 4985 CK1γ1(h) 2,568 4985 CK1γ2(h) 191 4985 CK1γ3(h) 4,7144985 CK1δ(h) >10,000 4985 CK1(y) 3,717 4992 CK1γ1(h) 4,543 4992 CK1γ2(h)745 4992 CK1γ3(h) 1,736 4992 CK1δ(h) >10,000 4992 CK1(y) 1,760 4996CK1γ1(h) 624 4996 CK1γ2(h) 27 4996 CK1γ3(h) >10,000 4996 CK1δ(h) >10,0004996 CK1(y) 2,447 5000 CK1γ1(h) 4,036 5000 CK1γ2(h) 2,367 5000 CK1γ3(h)3,498 5000 CK1δ(h) 9,153 5000 CK1(y) 1,719

The relative activity of the kinase as a function of the concentrationof the compounds are depicted in FIGS. 1-40.

Additional IC₅₀s for CK1 are shown in Table 6:

TABLE 6 CK1 IC₅₀ values (nM) ID CK1γ1 CK1γ2 IC₅₀ CK1γ3 10189 645 10190519 10196 63 10197 12 10202 529 102 700 10204 110 10205 127 38 131 102061254 77 566 10216 48

Additional % activity data is shown in Table 7.

TABLE 7 % Activity for various compounds ID CK1γ1 CK1γ2 CK1γ3 10190 8033 94 10204 14 7 31 10191 85 72 85 10205 15 2 8 10192 108 104 96 1020643 13 37 10193 97 94 93 10209 104 79 96 10194 92 79 78 10211 91 84 7910196 57 15 31 10212 99 99 99 10183 86 85 74 10197 14 −2 30 10214 98 10095 10200 82 59 77 10215 107 101 96 10202 38 15 38 10216 18 1 31 10189 6444 67 10203 78 71 80 10217 104 93 90

Example 236

PIM kinase assays were performed by Millipore UK Ltd. IC₅₀ data issummarized in Table 8, and percent activity data is summarized in Table9.

TABLE 8 PIM kinase IC₅₀ values ID Pim1 IC₅₀ (nM) Pim2 IC₅₀ (nM) Pim3IC₅₀ (nM) 4981 6348 1371 4991 1775 555 4980 5320 665 4982 287 256 49834328 3080 4989 4492 2051 4992 784 392 4993 189 91 191 4994 1578 786 49951819 2297 4998 4107 2741 5000 143 155 187 5117 3400 8996 10183 1332 73010212 304 477 10214 10216 499 163 10209 574 350 10202 857 108 10189 2966690 10200 3226 714 10190 3978 715 10191 2110 1310 10192 1655 2438 101932739 3846 10194 4399 2072 10206 3124 2217 10257 51 20 13 10256 45 47 27

TABLE 9 PIM kinase percent activity at varying concentrations % activity% activity % activity 10 microM 1 microM 10 microM PIM PIM PIM PIM PIMPIM PIM PIM ID 1 2 1 2 3 1 2 3 4848 37 34 4980 19 6 4982 2 8 4983 26 244985 30 23 4987 38 11 4989 23 19 4992 4 11 4993 0 9 4994 3 5 4995 14 204996 10 27 4997 18 11 4998 22 16 4999 27 10 5000 19 4 5001 17 16 5113 8654 5117 10 22 5121 105 61 5126 39 15 5132 86 61 5114 113 87 5118 92 505122 94 69 5127 61 67 5133 50 35 5115 77 63 5119 97 79 5124 88 59 5128108 64 5116 106 86 5120 95 62 5125 83 49 5131 117 83 5336 103 90 5337104 82 5338 117 103 5339 75 70 5340 98 78 5345 113 85 5349 101 94 5353109 101 5358 89 81 5341 107 109 5346 89 97 5350 76 97 5354 87 91 5343 7680 5347 87 105 5351 93 96 5355 50 52 5344 95 103 5348 83 92 5352 99 1035357 100 101 5359 94 99 5376 94 108 5382 80 101 5363 86 84 5378 88 925369 84 122 5379 81 107 5371 102 110 5380 93 114 10178 84 122 5134 51 4410179 63 81 10180 49 69 10181 74 93 10182 59 44 10183 8 7 10184 90 11510185 24 20 10227 88 10244 134 10247 121 10248 121 10249 122 10211 44 4110212 5 6 10214 51 44 10215 19 24 10216 8 21 10217 100 102 10209 11 810202 10 1 10189 14 4 10200 15 6 10190 16 9 10191 22 13 10192 23 2510193 20 24 10194 23 18 10196 65 80 10197 39 38 10203 35 52 10204 35 2310205 50 23 10206 18 17 10257 8 8 2 18 12 3 10256 9 12 0 24 28 8 10265 821 31 33 57 57 10264 20 30 17 49 49 46 10262 23 33 17 51 62 40 10255 3429 36 59 52 59 10259 57 72 48 80 97 67 10258 46 44 32 82 76 56 10251 6738 51 84 64 66 10253 67 63 54 87 81 79 10250 53 28 27 90 63 83 10263 7882 92 91 91 85 10260 50 63 33 94 79 60 10252 65 54 38 96 83 70 10254 7268 37 96 88 73 10261 82 99 62 100 117 87

Additional percent activity data at 10 micromolar (μM) for compounds4981 and 4991 is depicted in Tables 10 and 11.

TABLE 10 % Activity at 10 μM. ID GSK3β(h) Pim-1(h) Pim-2(h) Pim-3(h)VRK2(h) 4981 93 50 29 57 103 4991 66 20 15 73 103

TABLE 11 PI3 Kinase 4981 4991 PI3 (p110β/p85α)(h) 99 88 PI3 (p120γ)(h)85 61 PI3 (p110δ/p85α)(h) 86 45 PI3 (p110α/p85α)(m) 83 46 PI3(p110β/p65α)(m) 84 46 PI3 (p110α(E545K)/p85α)(m) 75 51 PI3(p110α(H1047R)/p85α)(m) 76 22 PI3 (p110β/p85β)(m) 99 86 PI3(p110β/p85α)(m) 95 85 PI3 (p110δ/p85α)(m) 85 57 PI3(p110α(E542K))/p85α)(h) 82 52 PI3 KC2 α(h) 90 84

Example 237 Cell Proliferation Studies

Inhibition of PC-3 cells:Cells: PC-3 cells, ATCC Passage unknown, Mycoplasma free.Medium: DMEM Medium (GIBCO Cat#11995073) supplemented with 10% fetalbovine serum (Hyclone Cat#SH30396.03).Seeding: 3,000 cells/well (100 μL) into 96-well plates, incubatedovernight at 37° C. in a humidified 5% CO₂ atmosphere.Treatment: Test compounds were first diluted 333-fold in the medium.Fifty microliters (50 μL) of diluted compounds were added into each well(i.e., another 3-fold dilution). The final concentration of testcompounds was 10 μM. The final concentrations of the positive control(Gemcitabine, also 50 μL added in each well) is shown in FIG. 41. Thecells were incubated for 72 hours after addition of the test compounds.MTS: Added 20 μL of MTS solution (Promega Cat #G5430) into each well andincubated for 4 hours.Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zeroctrl*100.

Results are shown in Table 12:

TABLE 12 Compound Test Color Inhibition ID No. OD value control Real ODAvg. Rate % 4981 1 2.004 2.010 1.893 0.676 1.329 1.334 1.218 1.294 0.84985 2 1.876 1.934 1.891 0.595 1.280 1.339 1.296 1.305 −0.1 4991 3 1.8041.851 1.775 0.599 1.205 1.252 1.176 1.211 7.1 4999 4 1.846 1.911 1.8240.590 1.256 1.321 1.234 1.270 2.6 Con — 1.679 2.079 1.915 0.587 1.0921.492 1.328 1.304 0.0  1.2 μM 1.783 1.800 1.833 0.587 1.196 1.213 1.2451.218 6.5  3.7 μM 1.769 1.800 1.841 0.587 1.182 1.213 1.253 1.216 6.711.1 μM 1.558 1.625 1.670 0.587 0.971 1.038 1.083 1.031 20.9 33.3 μM1.311 1.231 1.277 0.587 0.724 0.644 0.689 0.686 47.4  100 μM 1.145 1.1631.186 0.587 0.558 0.576 0.598 0.577 55.7  300 μM 0.805 0.925 0.833 0.5870.218 0.338 0.245 0.267 79.5

Example 238 Cell Proliferation Studies Inhibition of OVCAR-3 Cells

Cells: OVCAR-3 cells, ATCC Passage 4, Mycoplasma free.Medium: RPMI-1640 Medium (GIBCO Cat#22400121) supplemented with 10%fetal bovine serum (Hyclone Cat#SH30396.03).Seeding: 2,000 cells/well (100 μL) into 96-well plates, incubatedovernight at 37° C. in a humidified 5% CO₂ atmosphere.Treatment: Test compounds were first diluted 333-fold in the medium.Fifty microliters (50 μL) of diluted compounds were added into each well(i.e., another 3-fold dilution). The final concentration of testcompounds was 10 μM. The final concentrations of the positive control(Gemcitabine, also 50 μL added in each well) is shown in FIG. 42. Thecells were incubated for 72 hours after addition of the test compounds.MTS: Added 20 μL of MTS solution (Promega Cat #G5430) into each well andincubated for 4 hours.Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zeroctrl*100.

Results are shown in Table 13:

TABLE 13 Compound Test Color Inhibition ID No. OD value control Real ODAvg. Rate % 4981 1 0.777 0.872 0.917 0.267 0.510 0.606 0.650 0.589 19.24985 2 0.895 0.937 0.902 0.280 0.615 0.657 0.622 0.631 13.3 4991 3 0.5320.557 0.571 0.252 0.280 0.305 0.319 0.301 58.7 4999 4 0.794 0.882 0.7930.254 0.540 0.628 0.538 0.569 22.0 CON — 1.010 0.948 1.020 0.264 0.7460.684 0.756 0.728 0.0  1.2 μM 0.781 0.948 0.851 0.264 0.517 0.684 0.5860.596 18.2  3.7 μM 0.784 0.770 0.876 0.264 0.520 0.506 0.612 0.546 25.011.1 μM 0.742 0.749 0.797 0.264 0.478 0.485 0.532 0.499 31.5 33.3 μM0.638 0.687 0.760 0.264 0.374 0.423 0.496 0.431 40.8  100 μM 0.378 0.3310.408 0.264 0.114 0.067 0.144 0.108 85.1  300 μM 0.335 0.385 0.356 0.2640.071 0.121 0.092 0.095 87.0

Example 239 Cell Proliferation Studies Inhibition of LNCaP Cells

Cells: LNCaP, ATCC Passage unknown, Mycoplasma free.Medium: RPMI-1640 Medium (GIBCO Cat#22400121) supplemented with 10%fetal bovine serum (Hyclone Cat#SH30396.03).Seeding: 3,000 cells/well (100 μL) into 96-well plates, incubatedovernight at 37° C. in a humidified 5% CO₂ atmosphere.Treatment: Test compounds were first diluted 333-fold in the medium.Fifty microliters (50 μL) of diluted compounds were added into each well(i.e., another 3-fold dilution). The final concentration of testcompounds was 10 μM. The final concentrations of the positive control(Gemcitabine, also 50 μL added in each well) is shown in FIG. 43. Thecells were incubated for 72 hours after addition of the test compounds.MTS: Added 20 μL of MTS solution (Promega Cat #G5430) into each well andincubated for 4 hours.Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zeroctrl*100.

Results are shown in Table 14:

TABLE 14 Compound Test Color Inhibition ID No. OD value control Real ODAverage Rate % 4981 1 1.532 1.471 1.686 0.264 1.267 1.207 1.422 1.2994.1 4985 2 1.376 1.317 1.853 0.273 1.103 1.044 1.580 1.243 8.3 4991 31.328 1.361 1.414 0.267 1.061 1.094 1.147 1.100 18.8 4999 4 1.455 1.6021.584 0.283 1.173 1.319 1.301 1.264 6.7 Con — 1.714 1.505 1.647 0.2671.446 1.237 1.37 1.355 0.0  1.2 μM 1.403 1.394 1.480 0.267 1.135 1.1261.213 1.158 14.5  3.7 μM 0.730 0.814 0.847 0.267 0.463 0.547 0.579 0.53060.9 11.1 μM 0.379 0.410 0.413 0.267 0.112 0.142 0.145 0.133 90.2 33.3μM 0.363 0.375 0.353 0.267 0.096 0.107 0.086 0.097 92.9  100 μM 0.3770.406 0.396 0.267 0.109 0.139 0.128 0.126 90.7  300 μM 0.401 0.413 0.3910.267 0.134 0.145 0.123 0.134 90.1

Example 240 Cell Proliferation Studies Inhibition of Jurkat Cells

Cells: Jurkat cells, ATCC Passage unknown, Mycoplasma free.Medium: RPMI-1640 Medium (GIBCO Cat#22400121) supplemented with 10%fetal bovine serum(Hyclone Cat#SH30396.03).Seeding: 5,000 cells/well (100 μL) into 96-well plates, incubatedovernight at 37° C. in a humidified 5% CO₂ atmosphere.Treatment: Test compounds were first diluted 333-fold in the medium.Fifty microliters (50 μL) of diluted compounds were added into each well(i.e., another 3-fold dilution). The final concentration of testcompounds was 10 μM. The final concentrations of the positive control(Gemcitabine, also 50 μL added in each well) is shown in FIG. 44. Thecells were incubated for 72 hours after addition of the test compounds.MTS: Added 20 μL of MTS solution (Promega Cat #G5430) into each well andincubated for 4 hours.Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zeroctrl*100.

Results are shown in Table 15:

TABLE 15 Compound Test Color Inhibition ID No. OD value control Real ODAverage Rate % 4981 1 0.752 0.847 0.793 0.292 0.460 0.555 0.501 0.505−2.2 4985 2 0.660 0.620 0.613 0.302 0.357 0.318 0.311 0.329 33.5 4991 30.557 0.480 0.469 0.288 0.269 0.192 0.181 0.214 56.8 4999 4 0.718 0.6940.622 0.274 0.443 0.419 0.348 0.403 18.4 Con — 0.830 0.659 0.827 0.2780.552 0.382 0.548 0.494 0.0  1.2 μM 0.659 0.674 0.725 0.278 0.381 0.3960.447 0.408 17.4  3.7 μM 0.457 0.465 0.447 0.278 0.179 0.187 0.169 0.17963.9 11.1 μM 0.355 0.354 0.352 0.278 0.077 0.076 0.0742 0.076 84.7 33.3μM 0.254 0.249 0.254 0.278 −0.024 −0.029 −0.0234 −0.026 105.2  100 μM0.254 0.247 0.252 0.278 −0.024 −0.031 −0.0258 −0.027 105.5  300 μM 0.2610.258 0.255 0.278 −0.017 −0.020 −0.0231 −0.020 104.1

Example 241 Cell Proliferation Studies Inhibition of MDA-MB-468 Cells

Cells: MDA-MB-468 cells, ATCC Passage unknown, Mycoplasma free.Medium: RPMI-1640 Medium (GIBCO Cat#22400121) supplemented with 10%fetal bovine serum (Hyclone Cat#SH30396.03).Seeding: 2,000 cells/well (100 μL) into 96-well plates, incubatedovernight at 37° C. in a humidified 5% CO₂ atmosphere.Treatment: Test compounds were first diluted 333-fold in the medium.Fifty microliters (50 μL) of diluted compounds were added into each well(i.e., another 3-fold dilution). The final concentration of testcompounds was 10 μM. The final concentrations of the positive control(Gemcitabine, also 50 μL added in each well) is shown in FIG. 45. Thecells were incubated for 72 hours after addition of the test compounds.MTS: Added 20 μL of MTS solution (Promega Cat #G5430) into each well andincubated for 4 hours.Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zeroctrl*100.

Results are shown in Table 16:

TABLE 16 Compound Test Color Inhibition ID No. OD value control Real ODAverage Rate % 4981 1 0.733 1.158 0.739 0.334 0.400 0.824 0.405 0.54322.6 4985 2 0.845 1.107 0.893 0.280 0.565 0.828 0.613 0.669 4.7 4991 30.688 0.936 0.665 0.278 0.411 0.659 0.388 0.486 30.8 4999 4 0.800 1.1450.849 0.271 0.529 0.874 0.578 0.660 5.9 CON — 0.996 0.990 0.937 0.2730.723 0.717 0.663 0.702 0.0  1.2 μM 0.871 0.867 0.840 0.273 0.598 0.5940.567 0.586 16.4  3.7 μM 0.735 0.765 0.765 0.273 0.463 0.492 0.492 0.48231.2 11.1 μM 0.428 0.364 0.431 0.273 0.156 0.091 0.158 0.135 80.7 33.3μM 0.332 0.324 0.336 0.273 0.060 0.051 0.0629 0.058 91.7  100 μM 0.3310.318 0.405 0.273 0.058 0.045 0.132 0.078 88.8  300 μM 0.323 0.294 0.3090.273 0.050 0.022 0.0359 0.036 94.9

Example 242 Cell Proliferation Studies Inhibition of HCT116 Cells

Cells: HCT116 cells, ATCC Passage unknown, Mycoplasma free.Medium: DMEM Medium (GIBCO Cat#11995073) supplemented with 10% fetalbovine serum (Hyclone Cat#SH30396.03).Seeding: 750 cells/well (100 μL) into 96-well plates, incubatedovernight at 37° C. in a humidified 5% CO₂ atmosphere.Treatment: Test compounds were first diluted 333-fold in the medium.Fifty microliters (50 μL) of diluted compounds were added into each well(i.e., another 3-fold dilution). The final concentration of testcompounds was 10 μM. The final concentrations of the positive control(Gemcitabine, also 50 μL added in each well) is shown in FIG. 46. Thecells were incubated for 72 hours after addition of the test compounds.MTS: Added 20 μL of MTS solution (Promega Cat #G5430) into each well andincubated for 4 hours.Measurement: Absorbance at 490 nm using MD Spectramax Plus 384spectrophotometer.Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zeroctrl*100.

Results are shown in Table 17:

TABLE 17 Compound Test Color Inhibition ID No. OD value control Real ODAverage Rate % 4981 1 1.906 1.900 1.911 0.356 1.550 1.544 1.555 1.5508.9 4985 2 1.922 2.285 1.880 0.380 1.542 1.905 1.501 1.649 3.1 4991 31.750 1.645 1.744 0.352 1.399 1.293 1.392 1.361 20.0 4999 4 1.864 1.9791.997 0.357 1.506 1.621 1.640 1.589 6.6 CON control 2.034 1.970 2.1600.353 1.681 1.617 1.807 1.702 0.0  1.2 μM 1.171 1.242 1.192 0.353 0.8190.889 0.839 0.849 50.1  3.7 μM 0.707 0.640 0.768 0.353 0.355 0.287 0.4150.352 79.3 11.1 μM 0.573 0.565 0.653 0.353 0.220 0.213 0.300 0.244 85.633.3 μM 0.591 0.575 0.626 0.353 0.238 0.222 0.274 0.245 85.6  100 μM0.541 0.606 0.655 0.353 0.188 0.254 0.303 0.248 85.4  300 μM 0.546 0.5630.584 0.353 0.194 0.211 0.231 0.212 87.6

Example 243 Cell Proliferation Studies Inhibition of A549 Cells

Cells: A549 cells, ATCC Passage unknown, Mycoplasma free.Medium: DMEM Medium (GIBCO Cat#11995073) supplemented with 10% fetalbovine serum (Hyclone Cat#SH30396.03).Seeding: 750 cells/well (100 μL) into 96-well plates, incubatedovernight at 37° C. in a humidified 5% CO₂ atmosphere.Treatment: Test compounds were first diluted 333-fold in the medium.Fifty microliters (50 μL) of diluted compounds were added into each well(i.e., another 3-fold dilution). The final concentration of testcompounds was 10 μM. The final concentrations of the positive control(Gemcitabine, also 50 μL added in each well) is shown in FIG. 47. Thecells were incubated for 72 hours after addition of the test compounds.MTS: Added 20 μL of MTS solution (Promega Cat #G5430) into each well andincubated for 4 hours.Measurement: Absorbance at 490 nm using MD Spectramax Plus 384spectrophotometer.Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zeroctrl*100.

Results are shown in Table 18:

TABLE 18 Compound Test Color Inhibition ID No. OD value control Real ODAverage Rate % 4981 1 1.610 1.820 1.696 0.358 1.253 1.462 1.338 1.3512.9 4985 2 1.756 1.753 1.799 0.401 1.356 1.352 1.398 1.368 1.7 4991 31.632 1.602 1.611 0.306 1.326 1.295 1.305 1.309 6.0 4999 4 1.797 1.7381.789 0.387 1.410 1.351 1.402 1.388 0.3 CON control 1.848 1.806 1.5850.354 1.494 1.451 1.231 1.392 0.0  1.2 μM 1.197 1.282 1.158 0.354 0.8430.928 0.804 0.858 38.3  3.7 μM 0.840 0.864 0.854 0.354 0.485 0.510 0.5000.498 64.2 11.1 μM 0.733 0.750 0.762 0.354 0.378 0.396 0.407 0.394 71.733.3 μM 0.745 0.703 0.746 0.354 0.390 0.348 0.391 0.377 72.9  100 μM0.651 0.643 0.671 0.354 0.297 0.289 0.317 0.301 78.4  300 μM 0.629 0.5930.652 0.354 0.275 0.238 0.298 0.270 80.6

Example 244 Cell Proliferation Studies Inhibition of DU145 Cells

Cells: DU145 cells, ATCC Passage unknown, Mycoplasma free.Medium: DMEM Medium (GIBCO Cat#11995073) supplemented with 10% fetalbovine serum (Hyclone Cat#SH30396.03).Seeding: 750 cells/well (100 μL) into 96-well plates, incubatedovernight at 37° C. in a humidified 5% CO₂ atmosphere.Treatment: Test compounds were first diluted 333-fold in the medium.Fifty microliters (50 μL) of diluted compounds were added into each well(i.e., another 3-fold dilution). The final concentration of testcompounds was 10 μM. The final concentrations of the positive control(Gemcitabine, also 50 μL) added in each well) is shown in FIG. 48. Thecells were incubated for 72 hours after addition of the test compounds.MTS: Added 20 μl_, of MTS solution (Promega Cat #G5430) into each welland incubated for 4 hours.Measurement: Absorbance at 490 nm using MD Spectramax Plus 384spectrophotometer.Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zeroctrl*100.

Results are shown in Table 19:

TABLE 19 Compound Test Color Inhibition ID No. OD value control Real ODAverage Rate % 4981 1 1.360 1.205 1.427 0.259 1.100 0.946 1.168 1.0718.4 4985 2 1.522 1.724 1.551 0.411 1.112 1.314 1.140 1.188 −1.6 4991 31.487 1.516 1.512 0.367 1.120 1.149 1.145 1.138 2.7 4999 4 1.592 1.5911.538 0.290 1.302 1.302 1.248 1.284 −9.8 CON control 1.470 1.566 1.4690.332 1.138 1.234 1.137 1.170 0.0  1.2 μM 0.858 0.947 0.930 0.332 0.5260.615 0.598 0.580 50.4  3.7 μM 0.424 0.448 0.428 0.332 0.093 0.116 0.0970.102 91.3 11.1 μM 0.418 0.412 0.447 0.332 0.087 0.081 0.115 0.094 91.933.3 μM 0.404 0.425 0.457 0.332 0.072 0.093 0.125 0.097 91.7  100 μM0.453 0.426 0.355 0.332 0.121 0.094 0.023 0.079 93.2  300 μM 0.410 0.3950.400 0.332 0.079 0.063 0.068 0.070 94.0

Example 245 Cell Proliferation Studies Inhibition of HCC1954 Cells

Cells: DU145 cells, ATCC Passage unknown, Mycoplasma free.Medium: RPMI-1640 Medium (GIBCO Cat#22400121) supplemented with 10%fetal bovine serum (Hyclone Cat#SH30396.03).Seeding: 2,000 cells/well (100 μL) into 96-well plates, incubatedovernight at 37° C. in a humidified 5% CO₂ atmosphere.Treatment: Test compounds were first diluted 333-fold in the medium.Fifty microliters (50 μL) of diluted compounds were added into each well(i.e., another 3-fold dilution). The final concentration of testcompounds was 10 μM. The final concentrations of the positive control(Sorafenib, also 50 μL added in each well) is shown in FIG. 49. Thecells were incubated for 72 hours after addition of the test compounds.MTS: Added 20 μL of MTS solution (Promega Cat #G5430) into each well andincubated for 4 hours.Measurement: Absorbance at 490 nm using MD Spectramax Plus 384spectrophotometer.Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zeroctrl*100.

Results are shown in Table 20:

TABLE 20 Compound Test Color Inhibition ID No. OD value control Real ODAverage Rate % 4981 1 1.595 1.746 1.796 0.286 1.309 1.461 1.510 1.4272.2 4985 2 1.767 1.793 2.086 0.237 1.530 1.556 1.848 1.645 −12.8 4991 31.702 1.771 1.804 0.239 1.462 1.531 1.565 1.519 −4.2 4999 4 1.617 1.8231.816 0.227 1.389 1.596 1.589 1.525 −4.6 Con control 1.470 1.861 1.7720.243 1.227 1.618 1.529 1.458 0.0  1.2 μM 1.750 1.557 1.710 0.243 1.5071.314 1.467 1.429 2.0  3.7 μM 1.694 1.560 1.554 0.243 1.451 1.317 1.3111.360 6.8 11.1 μM 1.479 1.601 1.482 0.243 1.236 1.358 1.238 1.278 12.433.3 μM 0.296 0.265 0.275 0.243 0.053 0.022 0.032 0.036 97.5  100 μM0.324 0.309 0.313 0.243 0.081 0.066 0.070 0.072 95.0  300 μM 0.526 0.5220.539 0.243 0.283 0.279 0.296 0.286 80.4

Example 246 Cell Proliferation Studies Inhibition of Caco-2 Cells

Cells: Caco-2 cells, ATCC Passage 109, Mycoplasma free.Medium: DMEM Medium (GIBCO Cat#11995073) supplemented with 10% fetalbovine serum (Hyclone Cat#SH30396.03).Seeding: 3,000 cells/well (100 μL) into 96-well plates, incubatedovernight at 37° C. in a humidified 5% CO₂ atmosphere.Treatment: Test compounds were first diluted 333-fold in the medium.Fifty microliters (50 μL) of diluted compounds were added into each well(i.e., another 3-fold dilution). The final concentration of testcompounds was 10 μM. The final concentrations of the positive control(Sorafenib, also 50 μL added in each well) is shown in FIG. 50. Thecells were incubated for 72 hours after addition of the test compounds.MTS: Added 20 μL of MTS solution (Promega Cat #G5430) into each well andincubated for 4 hours.Measurement: Absorbance at 490 nm using MD Spectramax Plus 384spectrophotometer.Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zeroctrl*100.

Results are shown in Table 21:

TABLE 21 Compound Test Color Inhibition ID No. OD value control Real ODAverage Rate % 4981 1 1.392 1.571 1.473 0.391 1.001 1.180 1.082 1.0883.8 4985 2 1.535 1.572 1.512 0.351 1.184 1.221 1.160 1.188 −5.1 4991 31.319 1.287 1.344 0.367 0.952 0.920 0.977 0.949 16.0 4999 4 1.393 1.4851.432 0.342 1.051 1.143 1.090 1.094 3.2 Con control 1.415 1.516 1.4990.346 1.068 1.169 1.153 1.130 0.0  1.2 μM 1.528 1.497 1.430 0.346 1.1821.151 1.083 1.139 −0.7  3.7 μM 1.471 1.408 1.436 0.346 1.124 1.062 1.0891.092 3.4 11.1 μM 1.090 1.098 1.139 0.346 0.743 0.752 0.792 0.763 32.533.3 μM 0.393 0.383 0.366 0.346 0.047 0.037 0.020 0.034 96.9  100 μM0.418 0.396 0.392 0.346 0.072 0.050 0.045 0.056 95.1  300 μM 0.579 0.6000.638 0.346 0.233 0.253 0.292 0.259 77.1

Example 247 IC₅₀ Determination of Compound 4991 Against Three CancerCell Lines

Additional cell inhibition studies were performed by Crown Biosciences.The materials are described in Table 22.

TABLE 22 Human Positive Incubation cancer Cell line Medium drug timeOvary OVCAR-3 RPMI 1640 + 10% FBS Cisplatin 72 h cancer OVCAR-8 RPMI1640 + 10% FBS 72 h SK-OV-3 McCoy's 5a + 10% FBS 72 h

The dose response curves of compound 4991 compared to cisplatin, as wellas the calculated IC₅₀ values, are shown in FIGS. 51-53.

Example 248 In Vitro ADME Assays of PAMPA and Human and Rat HepaticMicrosomal Stability

The generic gradient HPLC and MS method summarized in Table 22 was usedfor the analysis of compounds 4981, 4985, 4991 and 4999.

TABLE 23 HPLC conditions. Instrument Applied Biosystems API 4000 massspectrometer Ionization Mode Electrospray, positive ions MRM 4981: 382.2→ 178.1 4985: 369.1 → 178.1 4991: 370.1 → 178.1 4999: 368.2 → 178.1Column ACE 2 C18, 2.1 × 50 mm, 3 μm Eluent A 2 mM ammonium acetate, 0.1%formic acid in 95:5 water:methanol Eluent B 2 mM ammonium acetate, 0.1%formic acid in 95:5 methanol:water Time (min) % A % B Pump Gradient 0 7525 Program 0.5 75 25 1.00 0 100 2.00 0 100 2.10 75 25 2.50 75 25 Flow(mL/min) 0.5 Column Temperature Ambient Injection Volume 3-30 SampleTemperature Ambient Run Time (min) 2.5

Parallel artificial membrane permeability assays (PAMPA) were performedwith the compounds 4981, 4985, 4991 and 4999. The target concentrationin the assay was 10 μM, prepared by diluting (1000-fold) the 10 mM stocksolutions in DMSO into PBS, pH 7.4. The final DMSO concentration was0.1%. The 10 μM solutions were added, 300 μL, to wells in the donorplate. The receiver plate, which contained 200 μL of PBS, pH 7.4 perwell, was placed in the donor plate and the assembly was incubated for 5hours at ambient temperature. At the end of the incubation period theplates were separated and the compound concentrations in each solutionwere determined by LC/MS/MS. The assay was performed in triplicate.Dexamethasone and verapamil were used as reference compounds. Thepermeability, P_(e), and mass retention, R, of each compound werecalculated using the following equations, and the results are summarizedin Table 17. The results for dexamethsone and verapamil were consistentwith historical data.

$P_{e} = \frac{{- {\ln \left\lbrack {1 - {C_{A{(t)}}/C_{0}}} \right\rbrack}} \times 10^{7}}{A \times \left( {{1/V_{D}} + {1/V_{A}}} \right) \times t}$$R = {1 - \frac{{C_{D{(t)}}V_{D}} + {C_{A{(t)}}V_{A}}}{C_{0}V_{D}}}$

Where:

C₀ is the initial concentration in the donor well (μM)C_(D(t)) is the concentration in the donor well after incubation (μM)C_(A(t)) is the concentration in the acceptor well after incubation (μM)V_(D) is the volume in the donor well (0.3 mL)V_(A) is the volume in the acceptor well (0.2 mL)

C_(E) is (C_(D(t))V_(D)+C_(A(t))V_(A))/(V_(D)+V_(A))

A is the filter area (0.3 cm2)t is the incubation time (18,000 s).

TABLE 24 PAMPA Assay data summary. Compound Permeability P_(e) (nm/s)Mass Retention R (%) 4981 6.0 0 4985 125 20 4991 99 0 4999 48 35Verapamil 75 20 Dexamethasone 9.0 9

Hepatic microsomal assays were performed with 4981, 4985, 4991 and 4999in human and rat (Sprague-Dawley). Protein concentrations of 0.4 (human)and 0.2 mg/mL (rat) with an NADPH regenerating cofactor system (2.6 mMNADP+, 6.6 mM glucose-6-phosphate, 0.8 U/mL glucose-6-phosphatedehydrogenase, and 6.6 mM magnesium chloride) were used. A 100 μM 20%DMSO/80% acetonitrile working stock of each of the compounds was diluted100 fold resulting in 1 μM compound/1% final organic reactionconcentrations. Time points were removed at 0 and 60 minutes. At eachtime point, 100 μL of the incubation suspension was added to 200 μL ofacetonitrile containing internal standard (tolbutamide), followed bycentrifugation at 3,220 rcf for 10 minutes. Two hundred (200)μL of theresulting supernatants were removed, dried under nitrogen andreconstituted in 100 μL of 2 mM ammonium acetate, 0.1% formic acid in50% methanol prior to analysis by LC/MS/MS. Testosterone anddexamethasone were used as reference compounds. Table 25 summarizes theresults. The results for testosterone and dexamethasone were consistentwith historical data.

TABLE 25 Hepatic microsomal stability summary % remaining afterincubation Compound Rat Microsomes Human Microsomes 4981 14 63 4985 0.446 4991 0.6 55 4999 0.4 3.6 Testosterone 0.6 42 Dexamethasone 91 85

Materials used are summarized in Table 26.

TABLE 26 Materials. Material Supplier Part No. Lot No. TestosteroneSigma T1500 087K1440 Dexamethasone Sigma D1756 096K1805 VerapamilAldrich 381195 12731MA Tolbutamide Sigma T0891 076K1277 PBS Sigma P3813096K8204 Ammonium acetate J.T. Baker 0599-08 E49H15 Formic acid AcrosOrganics 147930250 AO266198 Acetonitrile EMD AX0145-1  49099 DMSO AlfaAeser  32434 D04R008 Isopropanol J.T. Baker 9827-03 C38H23 Methanol EMDMX0486-1  49178 0.5M Potassium Phosphate BD Gentest 451201  06123 pH 7.4PAMPA plate BD Gentest 353015 431256 Human microsomes BD Gentest 452161 18888 Rat microsomes BD Gentest 452501  21027 NADPH Regeneration BDGentest 451220  51893 System Solution A NADPH Regeneration BD Gentest451220  47758 System Solution B water House DI (Barnstead Nanopure)

LC/MS Equipment: Chromatograph: Shimadzu LC-20 AD Autosampler: CTC HTSPAL MS: API 4000 Software System Analyst Software, Version 1.4.2.Example 249 Selected Cell Proliferation Inhibition Data Cell Lines:

Human Incubation cancer Cell line Medium Positive drug time MultipleMV4-11 IMDM Cisplatin 72 hours Myeloma RPMI-8226 RPMI-1640 NCI-H929RPMI-1640 + 0.05 mM 2-mercaptoethanol

All cells were cultured in media supplemented with 10% FBS except forwhich are marked specially, in the temperature of 37° C., 5% CO₂ and 95%humidity. All culture media were purchased from GIBCO (USA, IMDM Cat.12200-036; RPMI Medium 1640 Cat. 31800-022; 2-mercaptoethanol Cat.21985-023).

Reagents:

CellTiter 96® AQueous MTS reagent powder (Cat. No.: G11 12, Promega.Store MTS Reagent Powder desiccated at 4° C. protected from light.)Phenazine methosulfate (PMS) (Product No.: P9625, SIGMA. Store PMSPowder desiccated at 4° C. protected from light.)

Preparation of PMS Solution:

0.92 mg/mL PMS in DPBS Filter-sterilize through a 0.2 m filter into asterile, light-protected container. Store at −20° C.

Preparation of MTS Solution:

The following protocol is recommended for the preparation of 21 mL ofMTS solution (sufficient for ten 96-well plates).

-   a. Select a light-protected container or wrap a container with foil.-   b. Add 21 mL of DPBS to the container.-   c. Weigh out 42 mg of MTS Reagent Powder and add to DPBS.-   d. Mix at moderate speed on a magnetic stir plate for 15 minutes or    until the MTS is completely dissolved.-   e. Measure the pH of the MTS solution. The optimum pH is between pH    6.0 to 6.5. If the solution is above pH 6.5, adjust to pH 6.5 with    1N HC1.-   f. Filter-sterilize the MTS solution through a 0.2 μm filter into a    sterile, light protected container.-   g. Store the MTS solution at −20° C., protected from light.

Preparation of the Mixture of MTS/PMS:

-   a. In order to prepare reagents sufficient for one 96-well plate    containing cells cultured in a 100 μL volume, thaw the MTS solution    and the PMS solution. It should take approximately 90 minutes at    room temperature or 10 minutes in a 37° C. water bath to completely    thaw the 20 mL size of MTS solution. (Note: For convenience, the    first time the product is thawed, the entire contents of the 1 mL    tube of PMS solution can be transferred to the 20 mL bottle of MTS    solution. This mixture should be stored at −20° C. between uses. If    storing PMS and MTS solutions at 4° C., do not combine these    solutions until immediately before addition to the assay plate.)-   b. Remove 2.0 mL of MTS solution from the amber reagent bottle using    aseptic technique and transfer to a test tube.-   c. Add 100 μL of PMS solution to the 2.0 mL of MTS solution    immediately before addition to the culture plate containing cells.-   d. Gently swirl the tube to ensure complete mixing of the combined    MTS/PMS solution.

Equipment:

SpectraMAX plus microplate spectrophotometer Model 3011, MolecularDevices Corp. (California, USA); CO₂ water jacketed incubator, Therma(USA). Reverse microscope, Chongguang XDS-1B, Chongqing Guangdian Corp.(Chongqing, P.R. China).

Cytotoxicity and IC₅₀ Determination:

-   1. The cells were harvested respectively during the logarithmic    growth period and counted with hemocytometer. The cell viability was    over 98% by trypan blue exclusion.-   2. Cell concentrations were adjusted to 2.22×10⁵ or 1.11×10⁵ or    5.56×10⁴ cells/mL with respective medium.-   3. 90 μL cell suspensions were added to 96-well plates (triplicates    for each cell concentration), the final cell densities were 2×10⁴ or    1×10⁴ or 5×10³ cells/well. The density of 5×10³ cells/well was used    for the first test. The appropriate cell density was determined and    adjusted according to the results of the first test.-   4. The next day, test article or positive drugs were dissolved with    DMSO as stock solution at the concentration of 20 mM.-   5. 10 μL drug solution was dispensed in each well (triplicate for    each drug concentration).-   6. Plates were cultured for another 72 hours, then measured by means    of MTS assay.-   7. MTS/PMS solution was prepared immediately prior to use. 20 μL of    the mixture was introduced into each well of the 96-well assay plate    containing 100 μL culture medium. (The final reaction volume was 120    μL).-   8. Plate was incubated for 1-4 hours at 37° C. in a humidified 5%    CO₂ atmosphere.-   9. Absorbance at 490 nm was recorded using SpectraMAX Plus    microplate spectrophotometer.

Data Analysis:

The software of GraphPad Prism version 5 was used to calculate IC₅₀. Thegraphical curves were fitted using a nonlinear regression model with asigmoidal dose.

Results

Results are shown in Tables 27 and 28.

TABLE 27 IC₅₀ values (μM) Example MV4-11 RPMI 8226 NCI-H929 155 12.49 NC3.964 120 4.054 1.538 2.806 180 10.95 9.135 10.94 9 6.782 16.14 11.54181 1.199 3.412 4.415 182 2.025 11.87 7.076 183 1/829 9.604 4.603 1405.514 11.19 8.843 189 4.712 8.324 3.045 191 2.397 6.862 3.264

TABLE 28 Percent inhibition at 30 μM of Compound Example MV4-11 RPMI8226 NCI-H929 155 97.60 53.87 73.72 120 95.09 76.43 89.78 180 90.7179.74 100 9 91.08 71.25 91.44 181 96.63 82.15 93.5 182 91.09 90.21 96.52183 94.36 82.34 98.62 140 94.29 65.26 96.73 189 97.91 99.87 98.51 19187.43 93.08 93.96

Example 250

TABLE 29 Percent Activity of Enzyme When Treated with 300 nM of Compound(ATP present at Km of enzyme) Exam- Pim- Pim- Pim- ple CK1γ2(h) CK1(y)CK2(h) 1(h) 2(h) 3(h) 86 26 102 83 51 105 87 80 38 40 33 56 88 91 102 5254 102 89 100 82 99 116 110 90 81 38 22 22 62 91 79 57 36 32 102 92 10399 33 56 47 14 93 108 88 68 54 48 30 94 19 99 98 97 101 90 96 87 90 6573 44 57 97 83 101 70 49 22 69 98 67 89 59 40 27 39 99 85 96 79 39 6 4399 81 97 84 47 17 43 100 108 93 45 71 64 48 101 104 97 71 42 46 20 102101 101 84 94 91 53 103 90 97 73 114 138 99 104 89 99 82 75 72 42 105 9496 84 101 92 81 106 67 91 47 46 22 44 107 95 97 88 72 56 47 108 79 10090 49 18 57 109 82 82 59 68 49 57 110 58 94 62 54 31 48 111 102 104 9671 60 51 112 98 95 82 92 88 81 113 82 87 64 64 46 40 114 77 88 56 62 3642 115 55 94 67 50 28 55 116 83 96 61 59 45 57 117 71 91 67 37 16 53 11898 97 68 45 56 46 119 79 100 33 25 6 48 120 72 87 43 36 43 69 121 81 11555 74 37 82 122 64 96 71 43 50 68 123 71 99 106 92 94 109 124 92 110 9189 62 101 125 78 97 45 49 45 69 126 74 89 86 87 81 105 127 94 104 95 7782 86 128 52 97 86 75 84 99 129 85 87 76 99 87 100 130 96 92 64 94 85 96131 100 102 56 72 50 71 132 80 94 34 79 64 65 133 82 86 57 98 66 101 13431 77 57 102 88 118 135 82 99 69 59 48 82 136 36 101 71 80 49 72 137 97112 106 100 97 97 138 81 112 74 66 46 80 139 87 55 123 42 23 88 140 5279 26 45 53 48 142 96 103 85 84 87 143 78 79 15 14 3 3 144 103 81 5 2510 3 145 100 106 105 104 104 85 146 93 93 87 103 82 74 147 93 76 23 3325 8 148 98 88 42 70 40 25 149 107 108 53 74 40 49 150 97 97 77 49 29 23151 95 78 42 38 19 23 152 98 98 64 85 58 39 153 100 88 69 89 85 54 15498 106 77 45 30 16 155 98 88 74 7 12 5 156 83 99 54 83 68 87 157 63 8980 53 30 13 158 53 96 96 90 94 115 159 93 95 62 49 22 27 161 101 97 7131 46 30 162 97 101 73 86 67 76 163 94 105 108 99 90 100 164 112 98 10997 108 90 165 102 106 97 91 88 90 166 103 104 109 18 61 61 167 108 12791 14 44 2 168 100 99 48 47 82 171 101 103 79 96 95 89 172 105 96 81 3336 21 173 101 104 87 90 99 106 174 81 84 75 18 21 8 175 46 82 102 51 5761 176 86 87 67 28 34 15 177 87 86 76 22 26 12 178 91 101 75 105 89 96179 110 105 105 96 104 95 180 66 84 80 8 15 11 181 63 72 73 17 16 8 18256 86 61 9 10 4 183 91 60 73 5 7 3 184 84 95 81 19 28 9 185 87 91 71 2326 6 186 86 67 72 18 22 12 187 88 95 77 40 53 16 188 85 81 71 36 41 16189 33 38 49 1 6 3 190 60 64 73 3 16 2 191 65 64 63 4 14 4 192 52 95 8045 37 46 193 90 89 71 26 34 12 194 72 66 75 17 24 6 195 84 92 81 36 2511 196 99 99 93 50 55 51 197 102 106 94 43 58 54 198 104 106 98 60 44 36199 91 98 107 99 90 99 200 92 101 101 95 92 100 201 103 110 104 93 92106 202 84 97 85 84 72 87 203 95 103 84 25 58 51 204 91 86 74 19 40 25205 88 72 81 24 47 17 206 103 87 21 48 26 24 207 103 77 94 18 67 20 20899 104 39 36 17 21 209 91 106 54 42 41 42 211 54 93 106 71 24 61 212 2896 90 75 46 53 214 41 79 77 25 13 16 215 51 86 97 34 22 41 216 39 92 6040 10 76 217 109 116 101 91 105 218 82 80 96 91 100 219 55 100 58 57 4150 220 98 114 102 98 91 115 221 97 90 85 92 78 78 222 37 78 67 69 25 78223 28 100 89 56 23 79 224 53 64 71 16 15 9 225 66 91 67 61 47 55

Example 251

TABLE 30 IC₅₀ of Compound (nM) (ATP present at Km of enzyme) Exam- Pim-Pim- Pim- ple CK1γ2(h) CK1(y) CK2(h) 1(h) 2(h) 3(h) 86 86 87 261 295 80263 90 291 97 89 419 91 222 255 127 1000 92 186 628 228 31 94 38 98 422204 136 169 99 137 18 199 106 361 166 127 298 117 164 50 436 119 176 18616 267 120 676 >1000 214 170 225 271 143 66 20 5 3 144 23 78 18 9 147134 258 90 31 151 415 246 98 171 155 19 14 9 159 >1000 104 231 172 157142 46 174 58 75 16 176 669 487 108 18 177 705 96 87 22 180 13 15 15 18179 44 34 189 164 334 364 4 9 4 191 6 23 5 204 99 217 109 205 54 199 38208 129 288 43 65 214 95 35 60 219 476 475 146 249

INCORPORATION BY REFERENCE

All of the U.S. patents and U.S. published patent applications citedherein are hereby incorporated by reference.

EQUIVALENTS

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe scope of the present invention.

1-20. (canceled)
 21. A method of inhibiting CK1 activity, comprisingcontacting CK1, CK1γ1, CK1γ2, or CK1γ3 with a compound of formula 1:

or a pharmaceutically acceptable salt thereof, wherein independently foreach occurrence: W and X are independently oxygen or sulfur; Z¹, Z² andZ³ are independently C—R²⁰ or N, provided that at least one of Z¹ and Z²is N; R¹ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —COR^(E), —C(O)OR⁶, —SO₂(R⁶),—C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —[C(R⁴)₂]_(p)—R⁵; R² and R³ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)_(p)]—R⁵, —COR⁶, —C(O)OR⁶,—SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), —P(O)(OR⁶)(OR⁷); or R² and R³are joined together to form an optionally substituted heterocyclic ring;R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl,halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl; R⁵ is selectedfrom the group consisting of aryl, heteroaryl, heterocyclyl, —N(R⁸)(R⁹),—N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R⁸)SO₂(R⁹), —CON(R⁸)(R⁹), —OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR^(S), —C(O)N(OH)(R⁸),—OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR⁸, —OP(O)(OR⁸)(OR⁸),—P(O)(OR⁸)(OR⁸) and —N(R⁸)P(O)(OR⁹)(OR⁹); R⁶ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁷ isselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl; or R⁶ and R⁷ are joined together to form aheterocyclic ring; R⁸ is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, and heterocyclylalkyl; R⁹ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R⁸ andR⁹ are joined together to form a heterocyclic ring; R²⁰ is selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio,cyano, hydroxy, methoxy, alkoxy, phenoxy, aryloxy, heteroaryloxy,carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino,heteroarylamino, amido, acylamino, sulfate, sulfonate, sulfonyl,sulfoxido, sulfonamido, sulfamoyl, —[C(R⁴)₂]_(p)—R⁵, NR¹⁴R¹⁵, OR¹⁶,O—[C(R⁴)₂]_(p)—R⁵, NR¹⁴—[C(R⁴)₂]_(p)—R⁵ and SR¹⁶; R¹⁴ and R¹⁵ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶,—SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —P(O)(OR⁶)(OR⁷); or R¹⁴ andR¹⁵ are joined together to form an optionally substituted heterocyclicring; R¹⁶ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, and—C(O)N(R⁶)(R⁷); and p is 1, 2, 3, 4, 5, or 6; wherein any one of theaforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionallysubstituted.
 22. A method for treating or preventing a conditionassociated with aberrant CK1, CK1γ1, CK1γ2, or CK1γ3 activity,comprising administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of formula 1:

or a pharmaceutically acceptable salt thereof, wherein independently foreach occurrence: W and X are independently oxygen or sulfur; Z¹, Z² andZ³ are independently C—R²⁰ or N, provided that at least one of Z¹ and Z²is N; R¹ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —COR⁶, —C(O)OR⁶, —SO₂(R⁶),—C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —[C(R⁴)₂]_(p)—R⁵; R² and R³ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶,—SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), —P(O)(OR⁶)(OR⁷); or R² and R³are joined together to form an optionally substituted heterocyclic ring;R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl,halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl; R⁵ is selectedfrom the group consisting of aryl, heteroaryl, heterocyclyl, —N(R⁸)(R⁹),—N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R⁸)SO₂(R⁹), —CON(R⁸)(R⁹), —OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR⁹, —C(O)N(OH)(R⁸),—OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR⁸, —OP(O)(OR⁸)(OR⁸),—P(O)(OR⁸)(OR⁸) and —N(R⁸)P(O)(OR⁹)(OR⁹); R⁶ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁷ isselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl; or R⁶ and R⁷ are joined together to form aheterocyclic ring; R⁸ is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, and heterocyclylalkyl; R⁹ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R⁸ andR⁹ are joined together to form a heterocyclic ring; R²⁰ is selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio,cyano, hydroxy, methoxy, alkoxy, phenoxy, aryloxy, heteroaryloxy,carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino,heteroarylamino, amido, acylamino, sulfate, sulfonate, sulfonyl,sulfoxido, sulfonamido, sulfamoyl, —[C(R⁴)₂]_(p)—R⁵, NR¹⁴R¹⁵, OR¹⁶,O—[C(R⁴)₂]_(p)—R⁵, NR¹⁴—[C(R⁴)₂]_(p)—R⁵ and SR¹⁶; R¹⁴ and R¹⁵ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶,—SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —P(O)(OR⁶)(OR⁷); or R¹⁴ andR¹⁵ are joined together to form an optionally substituted heterocyclicring; R¹⁶ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, and—C(O)N(R⁶)(R⁷); and p is 1, 2, 3, 4, 5, or 6; wherein any one of theaforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionallysubstituted.
 23. A method of treating cancer, comprising administeringto a mammal in need thereof a therapeutically effective amount of acompound of formula 1;

or a pharmaceutically acceptable salt thereof, wherein independently foreach occurrence: W and X are independently oxygen or sulfur; Z¹, Z² andZ³ are independently C—R²⁰ or N, provided that at least one of Z¹ and Z²is N; R¹ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —COR^(E), —C(O)OR⁶, —SO₂(R⁶),—C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —[C(R⁴)₂]_(p)—R⁵; R² and R³ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶,—SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), —P(O)(OR⁶)(OR⁷); or R² and R³are joined together to form an optionally substituted heterocyclic ring;R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl,halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl; R⁵ is selectedfrom the group consisting of aryl, heteroaryl, heterocyclyl, —N(R⁸)(R⁹),—N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R⁸)SO₂(R⁹), —CON(R⁸)(R⁹), —OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR^(S), —C(O)N(OH)(R⁸),—OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR⁸, —OP(O)(OR⁸)(OR⁸),—P(O)(OR⁸)(OR⁸) and —N(R⁸)P(O)(OR⁹)(OR⁹); R⁶ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁷ isselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl; or R⁶ and R⁷ are joined together to form aheterocyclic ring; R⁸ is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, and heterocyclylalkyl; R⁹ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R⁸ andR⁹ are joined together to form a heterocyclic ring; R²⁰ is selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio,cyano, hydroxy, methoxy, alkoxy, phenoxy, aryloxy, heteroaryloxy,carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino,heteroarylamino, amido, acylamino, sulfate, sulfonate, sulfonyl,sulfoxido, sulfonamido, sulfamoyl, —[C(R⁴)₂]_(p)—R⁵, NR¹⁴R¹⁵, OR¹⁶,O—[C(R⁴)₂]_(p)—R⁵, NR¹⁴—[C(R⁴)₂]_(p)—R⁵ and SR¹⁶; R¹⁴ and R¹⁵ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶,—SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —P(O)(OR⁶)(OR⁷); or R¹⁴ andR¹⁵ are joined together to form an optionally substituted heterocyclicring; R¹⁶ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, and—C(O)N(R⁶)(R⁷); and p is 1, 2, 3, 4, 5, or 6; wherein any one of theaforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionallysubstituted.
 24. A method of treating Alzheimer's disease, comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of a compound of formula 1:

or a pharmaceutically acceptable salt thereof, wherein independently foreach occurrence: W and X are independently oxygen or sulfur; Z¹, Z² andZ³ are independently C—R²⁰ or N, provided that at least one of Z¹ and Z²is N; R¹ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —COR⁶, —C(O)OR⁶, —SO₂(R⁶),—C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —[C(R⁴)₂]_(p)—R⁵; R² and R³ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶,—SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), —P(O)(OR⁶)(OR⁷); or R² and R³are joined together to form an optionally substituted heterocyclic ring;R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl,halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl; R⁵ is selectedfrom the group consisting of aryl, heteroaryl, heterocyclyl, —N(R⁸)(R⁹),—N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R⁸)SO₂(R⁹), —CON(R⁸)(R⁹), —OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR⁸, —C(O)N(OH)(R⁸),—OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR⁸, —OP(O)(OR⁸)(OR⁸),—P(O)(OR⁸)(OR⁸) and —N(R⁸)P(O)(OR⁹)(OR⁹); R⁶ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁷ isselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl; or R⁶ and R⁷ are joined together to form aheterocyclic ring; R⁸ is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, and heterocyclylalkyl; R⁹ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R⁸ andR⁹ are joined together to form a heterocyclic ring; R²⁰ is selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio,cyano, hydroxy, methoxy, alkoxy, phenoxy, aryloxy, heteroaryloxy,carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino,heteroarylamino, amido, acylamino, sulfate, sulfonate, sulfonyl,sulfoxido, sulfonamido, sulfamoyl, —[C(R⁴)₂]_(p)—R⁵, NR¹⁴R¹⁵, OR¹⁶,O—[C(R⁴)₂]_(p)—R⁵, NR¹⁴—[C(R⁴)₂]_(p)—R⁵ and SR¹⁶; R¹⁴ and R¹⁵ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶,—SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —P(O)(OR⁶)(OR⁷); or R¹⁴ andR¹⁵ are joined together to form an optionally substituted heterocyclicring; R¹⁶ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, and—C(O)N(R⁶)(R⁷); and p is 1, 2, 3, 4, 5, or 6; wherein any one of theaforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionallysubstituted.
 25. A method of treating or preventing a disease orcondition selected from the group consisting of inflammation,inflammatory diseases, neurological conditions, and neurodegeneration,comprising administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of formula 1:

or a pharmaceutically acceptable salt thereof, wherein independently foreach occurrence: W and X are independently oxygen or sulfur; Z¹, Z² andZ³ are independently C—R²⁰ or N, provided that at least one of Z¹ and Z²is N; R¹ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —COR⁶, —C(O)OR⁶, —SO₂(R⁶),—C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —[C(R⁴)₂]_(p)—R⁵; R² and R³ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶,—SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), —P(O)(OR⁶)(OR⁷); or R² and R³are joined together to form an optionally substituted heterocyclic ring;R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl,halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl; R⁵ is selectedfrom the group consisting of aryl, heteroaryl, heterocyclyl, —N(R⁸)(R⁹),—N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R⁸)SO₂(R⁹), —CON(R⁸)(R⁹), —OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR⁸, —C(O)N(OH)(R⁸),—OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR^(S), —OP(O)(OR⁸)(OR⁸),—P(O)(OR⁸)(OR⁸) and —N(R⁸)P(O)(OR⁹)(OR⁹); R⁶ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁷ isselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl; or R⁶ and R⁷ are joined together to form aheterocyclic ring; R⁸ is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, and heterocyclylalkyl; R⁹ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R⁸ andR⁹ are joined together to form a heterocyclic ring; R²⁰ is selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio,cyano, hydroxy, methoxy, alkoxy, phenoxy, aryloxy, heteroaryloxy,carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino,heteroarylamino, amido, acylamino, sulfate, sulfonate, sulfonyl,sulfoxido, sulfonamido, sulfamoyl, —[C(R⁴)₂]_(p)—R⁵, NR¹⁴R¹⁵, OR¹⁶,O—[C(R⁴)₂]_(p)—R⁵, NR¹⁴—[C(R⁴)₂]_(p)—R⁵ and SR¹⁶; R¹⁴ and R¹⁵ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶,—SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —P(O)(OR⁶)(OR⁷); or R¹⁴ andR¹⁵ are joined together to form an optionally substituted heterocyclicring; R¹⁶ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, and—C(O)N(R⁶)(R⁷); and p is 1, 2, 3, 4, 5, or 6; wherein any one of theaforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionallysubstituted.
 26. A method of increasing apoptosis in cancerous cells,comprising administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of formula 1:

or a pharmaceutically acceptable salt thereof, wherein independently foreach occurrence: W and X are independently oxygen or sulfur; Z¹, Z² andZ³ are independently C—R²⁰ or N, provided that at least one of Z¹ and Z²is N; R¹ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —COR⁶, —C(O)OR⁶, —SO₂(R⁶),—C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —[C(R⁴)₂]_(p)—R⁵; R² and R³ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶,—SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), —P(O)(OR⁶)(OR⁷); or R² and R³are joined together to form an optionally substituted heterocyclic ring;R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl,halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl; R⁵ is selectedfrom the group consisting of aryl, heteroaryl, heterocyclyl, —N(R⁸)(R⁹),—N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R⁸)SO₂(R⁹), —CON(R⁸)(R⁹), —OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR⁹, —C(O)N(OH)(R⁸),—OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR⁸, —OP(O)(OR⁸)(OR⁸),—P(O)(OR⁸)(OR⁸) and —N(R⁸)P(O)(OR⁹)(OR⁹); R⁶ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁷ isselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl; or R⁶ and R⁷ are joined together to form aheterocyclic ring; R⁸ is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, and heterocyclylalkyl; R⁹ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R⁸ andR⁹ are joined together to form a heterocyclic ring; R²⁰ is selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio,cyano, hydroxy, methoxy, alkoxy, phenoxy, aryloxy, heteroaryloxy,carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino,heteroarylamino, amido, acylamino, sulfate, sulfonate, sulfonyl,sulfoxido, sulfonamido, sulfamoyl, —[C(R⁴)₂]_(p)—R⁵, NR¹⁴R¹⁵, OR¹⁶,O—[C(R⁴)₂]_(p)—R⁵, NR¹⁴—[C(R⁴)₂]_(p)—R⁵ and SR¹⁶; R¹⁴ and R¹⁵ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶,—SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —P(O)(OR⁶)(OR⁷); or R¹⁴ andR¹⁵ are joined together to form an optionally substituted heterocyclicring; R¹⁶ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, and—C(O)N(R⁶)(R⁷); and p is 1, 2, 3, 4, 5, or 6; wherein any one of theaforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionallysubstituted.
 27. A method of inhibiting PIM activity, comprisingcontacting PIM1, PIM2 or PIM3 with a compound of formula 1:

or a pharmaceutically acceptable salt thereof, wherein independently foreach occurrence: W and X are independently oxygen or sulfur; Z¹, Z² andZ³ are independently C—R²⁰ or N, provided that at least one of Z¹ and Z²is N; R¹ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —COR⁶, —C(O)OR⁶, —SO₂(R⁶),—C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —[C(R⁴)₂]_(p)—R⁵; R² and R³ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶,—SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), —P(O)(OR⁶)(OR⁷); or R² and R³are joined together to form an optionally substituted heterocyclic ring;R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl,halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl; R⁵ is selectedfrom the group consisting of aryl, heteroaryl, heterocyclyl, —N(R⁸)(R⁹),—N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R⁸)SO₂(R⁹), —CON(R⁸)(R⁹), —OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR⁹, —C(O)N(OH)(R⁸),—OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR⁸, —OP(O)(OR⁸)(OR⁸),—P(O)(OR⁸)(OR⁸) and —N(R⁸)P(O)(OR⁹)(OR⁹); R⁶ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁷ isselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl; or R⁶ and R⁷ are joined together to form aheterocyclic ring; R⁸ is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, and heterocyclylalkyl; R⁹ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R⁸ andR⁹ are joined together to form a heterocyclic ring; R²⁰ is selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio,cyano, hydroxy, methoxy, alkoxy, phenoxy, aryloxy, heteroaryloxy,carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino,heteroarylamino, amido, acylamino, sulfate, sulfonate, sulfonyl,sulfoxido, sulfonamido, sulfamoyl, —[C(R⁴)₂]_(p)—R⁵, NR¹⁴R¹⁵, OR¹⁶,O—[C(R⁴)₂]_(p)—R⁵, NR¹⁴—[C(R⁴)₂]_(p)—R⁵ and SR¹⁶; R¹⁴ and R¹⁵ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶,—SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —P(O)(OR⁶)(OR⁷); or R¹⁴ andR¹⁵ are joined together to form an optionally substituted heterocyclicring; R¹⁶ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, and—C(O)N(R⁶)(R⁷); and p is 1, 2, 3, 4, 5, or 6; wherein any one of theaforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionallysubstituted.
 28. A method for treating or preventing a conditionassociated with aberrant PIM activity, comprising administering to amammal in need thereof a therapeutically effective amount of a compoundof formula 1:

or a pharmaceutically acceptable salt thereof, wherein independently foreach occurrence: W and X are independently oxygen or sulfur; Z¹, Z² andZ³ are independently C—R²⁰ or N, provided that at least one of Z¹ and Z²is N; R¹ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —COR⁶, —C(O)OR⁶, —SO₂(R⁶),—C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —[C(R⁴)₂]_(p)—R⁵; R² and R³ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶,—SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), —P(O)(OR⁶)(OR⁷); or R² and R³are joined together to form an optionally substituted heterocyclic ring;R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl,halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl; R⁵ is selectedfrom the group consisting of aryl, heteroaryl, heterocyclyl, —N(R⁸)(R⁹),—N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R⁸)SO₂(R⁹), —CON(R⁸)(R⁹), —OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR⁹, —C(O)N(OH)(R⁸),—OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR⁸, —OP(O)(OR⁸)(OR⁸),—P(O)(OR⁸)(OR⁸) and —N(R⁸)P(O)(OR⁹)(OR⁹); R⁶ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁷ isselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, andheterocyclylalkyl; or R⁶ and R⁷ are joined together to form aheterocyclic ring; R⁸ is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, and heterocyclylalkyl; R⁹ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R⁸ andR⁹ are joined together to form a heterocyclic ring; R²⁰ is selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio,cyano, hydroxy, methoxy, alkoxy, phenoxy, aryloxy, heteroaryloxy,carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino,heteroarylamino, amido, acylamino, sulfate, sulfonate, sulfonyl,sulfoxido, sulfonamido, sulfamoyl, —[C(R⁴)₂]_(p)—R⁵, NR¹⁴R¹⁵, OR¹⁶,O—[C(R⁴)₂]_(p)—R⁵, NR¹⁴—[C(R⁴)₂]_(p)—R⁵ and SR¹⁶; R¹⁴ and R¹⁵ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶,—SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —P(O)(OR⁶)(OR⁷); or R¹⁴ andR¹⁵ are joined together to form an optionally substituted heterocyclicring; R¹⁶ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, and—C(O)N(R⁶)(R⁷); and p is 1, 2, 3, 4, 5, or 6; wherein any one of theaforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionallysubstituted.
 29. The method of claim 25, wherein the disease orcondition is inflammation.
 30. The method of claim 25, wherein thedisease or condition is osteoarthritis.
 31. The method of claim 25,wherein the disease or condition is rheumatoid arthritis.
 32. The methodof claim 25, wherein the disease or condition is neurodegeneration.